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PD Dr. med. Güliz Acker
Charité – Universitätsmedizin Berlin, Department of Neurosurgery with Pediatric Neurosurgery
Email: gueliz.acker@charite.de
Fields of Research
- Moyamoya Disease
- Glioblastoma Multiforme
- Vascular Targeting
- Brain Metastases
Project Title
Inhibition of the CXCL2/CXCR2 Signaling Pathway in Glioblastoma Multiforme as a Therapeutic Option
Project Description
Glioblastoma multiforme (GBM) is the most common and most malignant astroglial brain tumor with an overall median survival of around 15 months. Despite intensive research in recent decades on new therapeutic strategies no considerable advance in glioma treatment was achieved. Thus, novel and innovative therapeutic approaches are required to prolong survival and improve the quality of life for patients with malignant astroglial tumors. High angiogenesis of GBM is one of the causes of high malignancy, thus angiogenesis represents one of the promising therapeutic targets. However, the therapeutic effect of antiangiogenic treatments has been so far limited by diverse resistance mechanisms. Beside the strong vascularization of gliomas, a high accumulation of microglia/macrophages was shown. In addition, Roggendorf et al. proposed a direct correlation between the grade of gliomas and the number of tumor-associated microglia and macrophages. Therefore, these immune cells could represent an effective therapeutic target. We have already published that resident microglia are the main source of brain tumor mononuclear cells, thus these cells represent a promising novel therapeutic target for patients suffering from this tumor. We observed in our glioma mouse model that depletion of microglia/ macrophages resulted in diminished angiogenesis and reduced tumor volumes. We have also discovered a potential new feature of microglia/macrophages in a glioblastoma mouse model by secreting different chemokines. Due to high overexpression as well as indications in the literature the potential contribution of CXCL2 to glioma angiogenesis awakened our interest at most. Thus, the aim of our study it to establish a new therapy with blocking CXCL2 signal way induced angiogenesis in gliomas and to analyze the role of this pathway in recurrent GBM.
PD Dr. med. Lisa Christine Adams
Charité – Universitätsmedizin Berlin, Department of Radiology
Address: Charitéplatz 1, 10117 Berlin
Email: lisa.adams@charite.de
Fields of Research
- Molecular Imaging
- Aortic Aneurysms
- Quantitative MR Imaging
Project Title
Assessment of Abdominal Aortic Aneurysm Rupture Risk with Novel Molecular Imaging Techniques in an Experimental Mouse Model
Project Description
Abdominal aortic aneurysms pose an increasing burden to the healthcare system, accounting for a rising number of deaths. Currently, there is no biomarker available for the characterization of abdominal aortic aneurysms prior to rupture. The extracellular matrix is the most important structural component of the aortic wall, with extracellular matrix proteins such as elastin or collagen providing the tensile strength of the aortic wall, enabling it to with- stand the intraluminal hemodynamic forces. Apart from the extracellular matrix, proinflammatory cells (e.g. macrophages) play an important role in the initiation of ab- dominal aortic aneurysms and the degradation of extra- cellular matrix proteins. Based on the idea of abdominal aortic aneurysms being associated with pathological changes of the extracellular matrix, we aim to show that these changes can be visualized by in vivo magnetic resonance imaging. Recently, a small animal model based on the ApoE -/- mice has been established for detection of aortic disease, facilitating further investigation (Makowski et al., Nature Medicine 2011). We will use already established (elastin specific probe, very small iron oxide particles) and novel molecular probes (elastin with iron particles and collagen type I) for the non-invasive in vivo characterization and quantification of changes of the extracellular matrix, aiming to identify the most promising molecular probes and to test their potential to predict aortic rupture. In addition, the feasibility of these novel molecular probes to guide medical treatment will be investigated. The future aim for clinical translation is, that based on such target-specific molecular probes, clinicians will be able to monitor abdominal aortic aneurysm growth and also to reliably assess rupture risk, offering a personalized treatment.
PD Dr. med. Lisa Adams
Charité – Universitätsmedizin Berlin, Department of Radiology (including Pediatric Radiology)
Address: Charitéplatz 1, 10117 Berlin
Email: lisa.adams@charite.de
Fields of Research
- Molecular Imaging
- Aortic Aneurysms
- Quantitative MR Imaging
Project Title
Assessment of Abdominal Aortic Aneurysm Rupture Risk with Novel Molecular Imaging Techniques in an Experimental Mouse Model
Project Description
Abdominal aortic aneurysms pose an increasing burden to the healthcare system, accounting for a rising number of deaths. Currently, there is no biomarker available for the characterization of abdominal aortic aneurysms prior to rupture. The extracellular matrix is the most important structural component of the aortic wall, with extracellular matrix proteins such as elastin or collagen providing the tensile strength of the aortic wall, enabling it to with- stand the intraluminal hemodynamic forces. Apart from the extracellular matrix, proinflammatory cells (e.g. macrophages) play an important role in the initiation of ab- dominal aortic aneurysms and the degradation of extra- cellular matrix proteins. Based on the idea of abdominal aortic aneurysms being associated with pathological changes of the extracellular matrix, we aim to show that these changes can be visualized by in vivo magnetic resonance imaging. Recently, a small animal model based on the ApoE -/- mice has been established for detection of aortic disease, facilitating further investigation (Makowski et al., Nature Medicine 2011). We will use already established (elastin specific probe, very small iron oxide particles) and novel molecular probes (elastin with iron particles and collagen type I) for the non-invasive in vivo characterization and quantification of changes of the extracellular matrix, aiming to identify the most promising molecular probes and to test their potential to predict aortic rupture. In addition, the feasibility of these novel molecular probes to guide medical treatment will be investigated. The future aim for clinical translation is, that based on such target-specific molecular probes, clinicians will be able to monitor abdominal aortic aneurysm growth and also to reliably assess rupture risk, offering a personalized treatment.
Dr. med. Alessio Alogna, PhD
Charité – Universitätsmedizin Berlin, Department of Cardiology
Fields of Research
- Heart Failure
- Hemodynamics
- Nanotechnologies
Project Title
Inhalable Nanoparticle Formulations Targeting the Heart
Project Description
Heart failure is defined as the inability of the left ventricle to meet body’s demand at physiological filling pressures. Approximately 15 million Europeans and 6 million Americans suffer from HF, with annual direct and indirect costs in the billions. The prevalence of HF is about 1-2% in the adult population in western countries, and, given the aging of the population, epidemiologists al- ready in the early 90s predicted an exponential increase of HF incidence and prevalence in the upcoming de- cades. However, in spite of all medical efforts, the 5-year mortality of heart failure was decreased significantly less than that of malignant diseases. In fact, the day-to- day management of individual end-stage patients is still challenging with only short-term benefits, and heart transplantation is available only to a minority of patients. Altogether, this situation highlights the urgent need to overcome the difficulties associated with the use of conventional pharmacological therapies (i.e. drug instability, hampered efficacy and collateral side effects due to unspecific tissue targeting, invasive drug administration in end-stage disease) by developing novel groundbreaking therapeutic strategies that go far beyond any current conventional medical approach. Aim of this study is to provide a preclinical proof-of- concept for a non-invasive (via inhalation) nanoparticle-based delivery of therapeutic biomolecules to the diseased heart.
Dr. med. Alessio Alogna, PhD
Charité – Universitätsmedizin Berlin, Department of Cardiology
Fields of Research
- Heart Failure
- Hemodynamics
- Nanotechnologies
Project Title
Inhalable Nanoparticle Formulations Targeting the Heart
Project Description
Heart failure is defined as the inability of the left ventricle to meet body’s demand at physiological filling pressures. Approximately 15 million Europeans and 6 million Americans suffer from HF, with annual direct and indirect costs in the billions. The prevalence of HF is about 1-2% in the adult population in western countries, and, given the aging of the population, epidemiologists al- ready in the early 90s predicted an exponential increase of HF incidence and prevalence in the upcoming de- cades. However, in spite of all medical efforts, the 5-year mortality of heart failure was decreased significantly less than that of malignant diseases. In fact, the day-to- day management of individual end-stage patients is still challenging with only short-term benefits, and heart transplantation is available only to a minority of patients. Altogether, this situation highlights the urgent need to overcome the difficulties associated with the use of conventional pharmacological therapies (i.e. drug instability, hampered efficacy and collateral side effects due to unspecific tissue targeting, invasive drug administration in end-stage disease) by developing novel groundbreaking therapeutic strategies that go far beyond any current conventional medical approach. Aim of this study is to provide a preclinical proof-of- concept for a non-invasive (via inhalation) nanoparticle-based delivery of therapeutic biomolecules to the diseased heart.
PD Dr. med. Till Althoff
Dr. med. Judith Altmann
Charité – Universitätsmedizin Berlin, Department of Hematology, Oncology and Cancer Immunology
Email: judith.altmann@charite.de
Fields of Research
- Preeclampsia
- Oocyte-donation pregnancies
- Perinatal Medicine
- Obstetrics
Project Title
Immunological and cardiovascular inbalance in oocyte-donation pregnancies
Project Description
Our main research area is preeclampsia (PE), the sudden onset of hypertension (blood pressure > 140/90 mmHg) after the 20th week of pregnancy accompanied by proteinuria of >0,3g in 24 hours. Severe PE causes intrauterine growth restriction (IUGR) of the fetus, preterm delivery or even stillbirth. If PE is not detected and treated at an early stage, it leads to eclampsia, a tonic-clonic seizure, and a hypertensive crisis. During the seizure, the fetus might die within the uterus and the mother might suffer permanent cerebral damage if emergency Caesarean section is not performed immediately. Thus, PE is the leading cause of maternal and fetal morbidity and mortality, causing 20-25% of overall perinatal mortality and 16% of overall maternal mortality. The underlying pathomechanism of PE and the reliable prediction of the onset of the disorder are still unknown. However, it is evident that the placenta plays a major role in the development of this disease. In our clinical experience in one of the largest obstetric care units in Berlin (Charité), the number of pregnancies resulting from oocyte donation (OD) - performed abroad due to legal restrictions in Germany - rise continuously. Several studies conducted in OD pregnancies support the hypothesis that abnormal placentation owing to an immunological response of the mother to the fetus appears to be the cause of the high rate of PE in OD pregnancies. To investigate the pathway leading to preeclampsia we currently enroll pregnant women in prospective clinical trials, the “Berlin Brandenburg Pregnancy Cohort” and the “oocyte-donation pregnancy cohort” due to the high risk of preeclampsia in oocyte-donation pregnancies. During the visits, pregnant women are assessed using detailed cardiovascular and immunological phenotyping at three time points during the pregnancy, at delivery and 2-5 years after pregnancy (to further reveal the cardiovascular long term consequence of PE).
The aim of this study is to develop a profound understanding of the immune cells playing a pivotal role at the fetal-maternal interface and their role in the development of preeclampsia in oocyte-donation pregnancies via single-nucleus RNA sequencing (sNuc-Seq) using samples from healthy controls and preeclamptic pregnancies resulting from Berlin and Oslo cohorts. Furthermore, we plan to process a subset of samples for spatial transcriptomics.Dr. med. Dipl. phys. Christopher Maximilian Arends
Charité – Universitätsmedizin Berlin, Department of Hematology, Oncology and Cancer Immunology
Email: christopher-maximilian.arends@charite.de
Fields of Research
- Clonal hematopoiesis
- Myeloid Malignancies
- Tumor Genetics
Project Title
Clinical Implications of Clonal Hematopoiesis Under Different Stress Scenarios
Project Description
Ageing is strongly associated with an increasing risk of cardiovascular disease and cancer. Recently, an interesting common driver of these two age-associated diseases has been discovered: clonal hematopoiesis (CH), defined by the acquisition of somatic mutations in hematopoietic stem cells, occurs in 20-30% of individuals > 60 years and is associated with a higher overall mortality, an increased risk for cardiovascular events, and a ten-fold risk for the development of hematologic malignancies. Interestingly, a causal relation between CH and the progression of coronary heart disease driven by an altered inflammatory function of mature mutated monocytes/ macrophages has been described in preclinical models. These and other recent data pinpoint towards pleiotropic effects of mutated clones in individuals with CH, not only affecting self-renewal and differentiation but also inflammatory signaling of mature blood cells, which become particularly pronounced in certain stress scenarios such as cytotoxic chemotherapy, allogeneic stem cell transplantation and inflammation. The aim of this interdisciplinary project is to investigate the clinical implications of CH in different stress scenarios. Inflammation plays a crucial role in the pathogenesis of ischemic stroke and its functional outcome after brain injury. However, despite its indisputable relevance on epidemiologic scales, the role of CH in the context of ischemic stroke remains elusive. Applying bulk and single-cell sequencing techniques to bio-banked blood samples from the Prospective Cohort with Incident Stroke Berlin (PROSCIS-B), I address the role of CH in patients suffering from ischemic stroke with respect to functional outcome and risk for recurrent vascular events. A second focus of the project is on CH in patients with non-hematologic malignancies. By integrating sequencing data with clinical data from a large phase III study of patients with metastasized colorectal cancer (FIRE-3), I aim to delineate the implications of CH on treatment outcome and analyze the clonal evolution of CH under the selective pressure of cytotoxic treatment. With the results I hope to contribute to a better understanding of this interesting new commonality between cardiovascular disease and cancer.
Dr. med. Viktor Arnhold
Charité – Universitätsmedizin Berlin, Department of Pediatrics, Division of Oncology and Hematology
Email: viktor.arnhold@charite.de
Fields of Research
- Neuroblastoma
- Signal transduction pathways
Project Title
Pharmacological Reactivation of the P53 Pathway by DS3032b in Neuroblastoma
Project Description
Neuroblastoma is the most common extracranial childhood tumor. Despite aggressive multimodal therapy, survival of patients with high-risk neuroblastoma, which represent the majority of neuroblastoma patients, is <40% and the outcome of patients with relapsed neuroblastoma is almost always fatal. In addition, side effects of current multimodal therapeutic regimens for the treatment of neuroblastoma are high, often resulting in lifelong sequelae in survivors. Therefore, the development of targeted approaches with fewer adverse effects is of major importance for patients with primary high risk or relapsed neuroblastoma, who are in urgent need of additional effective therapies. The tumor suppressor gene TP53 is involved in the formation of different malignancies. Inactivating mutations in the TP53 gene are rare in neuroblastoma, but overexpression of MDM2 resulting in functional p53 inactivation is commonly detected. Specific antitumor activity of compounds targeting the p53-MDM2 axis has been demonstrated. Treatment with MDM2 inhibitors reduced cell viability in vitro and in vivo by re-activating p53 function. On the basis of the existing data, functional reactivation of p53 and/or inhibition of the p53/MDM2 axis in neuroblastoma are therefore promising therapeutic options. A prerequisite to clinical testing of DS3032b in patients with neuroblastoma is the comprehensive preclinical evaluation of the antitumor effect of this compound against neuroblastoma cells in vitro and in vivo. As a basis for clinical testing of DS3032b in neuroblastoma patients, we will analyze the effect of these compounds on cell lines in vitro and in subcutaneous xenograft models in vivo. In a first step, we plan to analyze the antitumor activity of DS3032b using cell growth, proliferation, senescence and apoptosis assays, flow cytometer, Western blotting and reverse transcription-quantitative PCR (RT-qPCR) analysis of p53 target genes. The specificity of the effect of DS3032b treatment should be detected by »rescue« experiments. In addition, we want to examine the activity of DS3032b in a subcutaneous xenograft mouse model.
PD Dr. med. Viktor Arnold
PD Dr. med. Georgi Atanasov
Charité – Universitätsmedizin Berlin, Department of Surgery
Email: geshaman@hotmail.com
Fields of Research
- Hepato‐Biliary Tumors
- Cancer Immunity
- Monocytes/Macrophages
Project Title
The Role of CD39+ Foxp3+ Regulatory T-Cells in Cholangiocarcinoma Progression
Project Description
Hepatocarcinogenesis is associated with chronic inflammation, which is linked to immune dysregulation. The role of purinergic signaling in hepatocarcinogenesis is poorly understood. Disordered purinergic signaling via receptors for danger-associated molecular patterns (DAMPs), i.e. adenosine triphosphate (ATP) and adenosine diphosphate (ADP), is associated with carcinogenesis. Nucleoside triphosphate diphosphohydrolase-1 (CD39/ENTPD1) is an ectonucleotidase that regulates these extracellular nucleotide/nucleoside concentrations by scavenging nucleotides to ultimately generate adenosine. CD39/ENT- PD1 is the dominant ectonucleotidase expressed by regulatory T-cells (Tregs). CD39 drives the sequential hydro- lysis of both ATP and ADP to AMP. Adenosine promotes immune suppression and tumor progression by stimulating vascular endothelial cell proliferation, and inhibiting immune cell cytokine synthesis, transendothelium migration, and anti-tumor effector responses. Taken together, these properties inhibit anti-tumor immune responses and promote angiogenesis. Based on our previous findings implicating key role of monocytes/macrophages in hepatobiliary tumors (Atanasov et al. OncoImmunology 2017), we hypothesize their function to be mechanistically modulated in a CD39-dependent manner. With this in mind, we (a) established a tumor model in mice emulat- ing human hepatocarcinogenesis and (b) were able to demonstrate presence of functionally active purinergic receptors on human monocytes/macrophages. We investigate the impact of CD39 activity on Tregs on tumor progression by performing adoptive cell therapy with CD39+ or CD39- Tregs in tumor induced nude mice. We previously reported angiogenic monocytes/macrophages to associate with tumor growth, metastasis, recurrence and clinical prognosis in primary liver malignancies (Atanasov et al. J Surg Oncol 2016). Consequently, we fo- cus especially on cytokine levels, apoptosis rate and purinergic receptor profiles, as well as immune cell responses and infiltrates. By performing pharmacologic blockade with POM-1, a selective inhibitor of CD39 activity, and consecutively reducing extracellular adenosine concentrations, we will investigate therapeutic effects in tumor nude mice reconstituted with CD39+ Tregs and wild type tumor mice. A successful chemotherapy implies that an immunologic checkpoint inhibition of CD39 enzymatic activity may find utility as an adjunct therapy for hepatic malignancies.
Dr. med. Martin Atta Mensah
Charité – Universitätsmedizin Berlin, Institute of Medical Genetics and Human Genetics
Email: martin‐atta.mensah@charite.de
Fields of Research
- Exomics
- Syndromology
- Computer‐Aided Photogrammetry
Project Title
Prioritization of Exome Data by Image Analysis
Project Description
The rapid development of new sequencing methods (Next Generation Sequencing) enables the fast and cost-effective analysis of all human genes. This development presents human genetics and in particular clinical genetics with the challenges of interpreting the large amounts of generated data. Among the thousands of neutral sequence variants, the one pathogenic mutation has to be found. Various bioinformatic approaches have been developed, which are based on the clinical-phenotypic description of the investigated patient (physical appearance, symptoms, laboratory findings ...) and on the properties of the detected variants (altered gene, allele frequency, degree of evolutionary conservation, type of variant ...). These methods offer good results, but there is still room for improvement. In clinical genetics, the face of a patient traditionally plays a key role in determining the diagnosis as approx. 40% of hereditary syndromological diseases show characteristic abnormalities of the facial morphology. Knowledge of these abnormalities is therefore of particular value for the clinical geneticist. The large number of hereditary syndromes (there are several thou- sand) and the rarity of the individual disease entities re- quire expertise based on decades of clinical experience. Modern machine-learning based image recognition pro- grams are able to learn these specific features of the facial gestalt from ordinary frontal photos of patients with genetic-syndromological diseases. Our research aims to evaluate these methods and to develop a machine-learning based pipeline, which– in addition to prior approaches- includes automated facial photogrammetry in sequence data analysis to enable an even more efficient diagnostic procedure.
Dr. med. Aline Azabdaftari
Charité – Universitätsmedizin Berlin, Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine
Email: aline.azabdaftari@charite.de
Fields of Research
- Paediatric gastroenterology
- Inflammatory bowel disease
- Epithelial immunology
Project Title
Expression and Regulation of Interleukin-37 in Human Intestinal Epithelium During Health and Infl ammatory Bowel Disease
Project Description
The incidence of inflammatory bowel diseases (IBD) is markedly rising in industrialized countries, with 25% of patients being newly diagnosed in childhood and adolescence. Alterations of the epithelial barrier appear to contribute towards generating a dysbalance of the intestinal immune response in genetically susceptible individuals. Investigating the interplay of the intestinal epithelial barrier and the gut immune system in health and disease is crucial to understand the pathogenesis of IBD and to improve future treatment strategies. The epithelium is part of the intestinal immune system, producing antimicrobial peptides and interacting with immune cells through the release of immunomodulatory cytokines. Interleukin-37 (IL-37) is an anti-inflammatory member of the IL-1 cytokine family. It has been shown to protect mice from colitis and a homozygous mutation led to infantile onset IBD in a patient. The role of IL-37 has mainly been investigated in the immune cell compartment. However, our recent studies also showed IL-37 protein expression in the intestinal epithelium. We hypothesize that IL-37 contributes to the immune homoeostasis of the gut and plays a crucial role as an anti-inflammatory cytokine regulating intestinal epithelial function. The aim of this project is to understand the expression and regulation of IL-37 in the human intestinal epithelium. We investigate the expression of IL-37 and related genes using existing bulk transcriptomic datasets of children with newly diagnosed IBD and healthy controls (1). Using in vitro experiments, we explore the regulation of IL-37 expression in the human intestinal epithelium. We therefor generate patient-derived intestinal epithelial organoids as a model system (2). We then stimulate the intestinal organoids with different cytokines known to be involved in the pathogenesis of IBD (2) and investigate the time course of IL-37 mRNA expression (3). These experiments will contribute to our understanding of the expression and regulation of IL-37 in the human intestinal epithelium. Functional studies are currently performed and will further help to unravel the role of IL-37 in the pathogenesis of IBD.
PD Dr. med. Magdalena Balcerek
Charité – Universitätsmedizin Berlin, Department of Pediatrics, Division of Oncology and Hematology
Email: magdalena.balcerek@charite.de
Fields of Research
- Paediatric Oncology and Haematology
- Fertility Impairment
- Quality of Life
Project Title
FeCt Hematology, Fertility in Patients with Hematologic Diseases
Project Description
Diseases causing chronic anaemia require constant monitoring and treatment to avoid potentially life-threatening complications. Improvements in medical treatment in recent years has notably raised patient prognosis. Therefore, long-term consequences of the underlying disease and/or the necessary treatments as well as quality of life of those affected are of increasing relevance. A key aspect of high quality of life is successful family planning. However, patients with different anaemia may suffer from fertility impairment. FeCt-HAEMATOLOGY aims to identify prevalences, disease and therapy-related risk factors and dynamics of fertility impairment in adolescents and adults with different anaemia as well as the psycho-social relevance of successful family planning for those affected. The study will be conducted as a multicentre retro- and prospective study in cooperation with disease-specific registries and working groups in centres for paediatric and internal medicine in Germany, Austria and Switzerland. The psycho-social relevance of successful family planning, patient education and utilization of fertility preservation will be assessed with the help of a patient questionnaire. Medical data, such as patient core data (sex, date of birth, diagnosis and date of diagnosis) and data on pubertal development, pregnancies and births as well as clinical and laboratory findings, results of fertility testing and therapy data will be collected from patient files/ data bases for data analyses. Findings will be distributed to the disease- and treat- ment-specific registries and working groups. Project output will help to (1) improve therapeutic strategies to reduce adverse late effects, (2) assist therapists and patients in optimizing family planning and (3) determine timing and choice of fertility-preserving measures and/or reproductive therapies.
Dr. med. Magdalena Balcerek
Charité – Universitätsmedizin Berlin, Department of Pediatrics, Division of Oncology and Hematology
Email: magdalena.balcerek@charite.de
Fields of Research
- Paediatric Oncology and Haematology
- Fertility Impairment
- Quality of Life
Project Title
Prevalences, Risk Factors and Dynamics of Fertility Impairment in Patients with Chronic Anaemia
Project Description
Diseases causing chronic anaemia require constant monitoring and treatment to avoid potentially life-threatening complications. Improvements in medical treatment in recent years has notably raised patient prognosis. Therefore, long-term consequences of the underlying disease and/or the necessary treatments as well as quality of life of those affected are of increasing relevance. A key aspect of high quality of life is successful family planning. However, patients with different anaemia may suffer from fertility impairment. FeCt-HAEMATOLOGY aims to identify prevalences, disease and therapy-related risk factors and dynamics of fertility impairment in adolescents and adults with different anaemia as well as the psycho-social relevance of successful family planning for those affected. The study will be conducted as a multicentre retro- and prospective study in cooperation with disease-specific registries and working groups in centres for paediatric and internal medicine in Germany, Austria and Switzerland. The psycho-social relevance of successful family planning, patient education and utilization of fertility preservation will be assessed with the help of a patient questionnaire. Medical data, such as patient core data (sex, date of birth, diagnosis and date of diagnosis) and data on pubertal development, pregnancies and births as well as clinical and laboratory findings, results of fertility testing and therapy data will be collected from patient files/ data bases for data analyses. Findings will be distributed to the disease- and treat- ment-specific registries and working groups. Project output will help to (1) improve therapeutic strategies to reduce adverse late effects, (2) assist therapists and patients in optimizing family planning and (3) determine timing and choice of fertility-preserving measures and/or reproductive therapies.
Dr. med. Alexej Ballhausen
Email: alexej.ballhausen@charite.de
Fields of Research
- Multiple Myeloma
- Clonal evolution
- Single cell technologies
Project Title
Cellular relatedness and genetic diversity of multiple myeloma at the single cell level
Project Description
Multiple myeloma is a hematologic malignancy characterized by accumulation of monoclonal plasma cells in the bone marrow. Extensive bone marrow infiltration and production of monoclonal immunoglobulin or light chains can cause life-threatening complications including infections, renal failure, amyloidosis, bone fractures, and bone marrow failure, among others. Although a variety of novel treatment options can induce remissions, multiple myeloma frequently relapses and remains incurable. Due to the nature of the disease (malignancy of the B lineage), multiple myeloma cells within individual patients carry identical immunoglobulin sequences, which can be used as highly sensitive biomarkers and characteristic molecular barcodes to track the disease. In addition, a variety of somatic mutations have been identified in multiple myeloma. However, the impact of distinct mutational patterns or distinct B cell populations on disease progression remains unclear. Moreover, the cell of origin in multiple myeloma has been under debate. Although accumulating malignant cells are predominantly plasma cells and substantial numbers of somatic hypermutations within immunoglobulin genes suggest that the disease arises at the post-germinal center stage of B cell development, their immune phenotypes can be diverse and include even normal-phenotype B cells.
We aim to 1) define the phenotypic range of multiple myeloma at the single cell level, 2) identify developmental trajectories of monoclonal B lineage cells and 3) identify populations at developmentally early stages for selective isolation and translational therapeutic targeting. We will determine high-dimensional immune phenotypes, immunoglobulin sequences, and somatic mutations in parallel at the single cell level in thousands of bone marrow B lineage cells from 15 treatment-naïve multiple myeloma patients. This project addresses the unmet medical need to identify cell populations that are critically involved in multiple myeloma development and represent potential targets for translational therapeutics.Dr. med. Lorenz Bastian
Charité – Universitätsmedizin Berlin, Medical Department, Division of Hematology and Oncology
Email: lorenz.bastian@charite.de
Fields of Research
- Acute Lymphoblastic Leukemia
- Molecular Leukemogenesis
- Genotype Informed Treatments
Project Title
Oncogenic Drivers in the Molecular Pathogenesis of Acute Lymphoblastic Leukemia
Project Description
The prognosis of adult patients suffering from B cell precursor acute lymphoblastic leukemia (BCP-ALL) is still poor, especially in case of relapsed disease. Detailed knowledge of leukemogenic drivers is required for targeted therapeutic interventions. We integrate high resolution profiling of gene fusions, sequence mutations, copy number alterations as well as gene expression- and DNA methylation profiles together with clinical phenotypes to characterize novel drivers and resistance factors in BCP-ALL. With-in a cohort of 250 BCP-ALL patients we have established a novel molecular subgroup by a dis- tinct gene expression and DNA methylation profile. We identified a combination of sequence mutations in the hematopoietic transcription factor PAX5, copy number loss in the cell cycle regulator CDKN2A and activating RAS/MAPK- or JAK/STAT-pathway mutations as bonafide drivers of the disease these patients, thus representing an interesting disease model where hallmark signaling pathways each are affected by a single defined alteration. Analyzing a cohort of 90 matched diagnosis – relapse sample pairs, we observed the frequent acquisition of mutations in histone methylation regulators during BCP-ALL relapse. We perform ChIP-Seq analysis of mutated primary patient samples and cell line models to delineate the impact of these alterations on gene regulation. Using CRISPR genome editing, we create functional models of the identified mutations to dissect the signaling mechanisms involved and to validate potential therapeutic targets. Further oncogenic signaling dependencies are explored in a drug sensitivity profiling of primary BCP-ALL samples and cell lines with defined genomic background. Together, these analyses provide the framework for a molecular tumor board to guide individual treatment decisions in relapsed/refractory BCP- ALL. Together with our cooperation partners, we are currently developing this tumor board within the German Acute Lymphoblastic Leukemia Study group.
Dr. med. Francis Baumgartner
Charité – Universitätsmedizin Berlin, Department of Hematology, Oncology and Cancer Immunology
Email: francis.baumgartner@charite.de
Fields of Research
- ASXL1-mutated leukemias
- IL6-STAT3 signalling in autoimmunity
- SUMOylation in Multiple Myeloma
Project Title
Forward Genetic Screen for Functional Characterization of ASXL1-Mutated Leukemias
Project Description
The epigenetic regulator Additional sex combs like 1 (ASXL1) is one of the most frequently mutated genes in hematopoietic malignancies. ASXL1 mutations (ASXL1mut) can be detected in up to 20% of patients* with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) as well as other myeloid neoplasms and are prognostically unfavorable, especially in combination with known driver mutations such as DNMT3A, JAK2, TET2 and TP53. However, the exact mechanisms of ASXL1mut-mediated malignant transformation are poorly understood and no targeted therapeutic strategy exists, thus there is great clinical need for improved molecular understanding, establishment of predictive biomarkers, and development of targeted therapeutics. Large AML sequencing studies over the past decade have cataloged gene mutations and epigenetic alterations and identified numerous prognostically relevant genes. However, identification of mutations causal for disease development and persistence and translation of these findings into clinical therapeutic strategies is currently very limited. Thus, only a few molecularly addressable mutations have been identified so far, which is why the prognosis of AML patients has hardly improved over the last decades. PiggyBac transposon mutagenesis screening is a powerful murine model system in which genome-wide in vivo screening for relevant genes in oncogenesis is feasible by random activation and inactivation of all genes and regions. PB transposons are short DNA elements that randomly integrate and de-integrate throughout the genome through PB transposase activity, resulting in a functionally relevant growth advantage in some cells via oncogene activation or tumor suppressor inactivation. Integration sites are then characterized at high resolution and classified as statistically relevant affected common integration sites. In this research project, a forward-genetics in vivo screen will identify genomic networks associated with ASXL1mut, which will be further addressed experimentally in follow-up projects. The central research question is which genes in combination with ASXL1mut are drivers of leukemogenesis and how ASXL1mut contributes to leukemogenesis through epigenetic dysregulation.
Dr. med. Nikolaus Behr
Charité – Universitätsmedizin Berlin, Department of Neurology and Experimental Neurology
Email: nikolaus.behr@charite.de
Fields of Research
- Neuro-Oncology
- Molecular Diagnostics
- Bioinformatics
Project Title
Methylation-Based Classifi cation of Cell-Free DNA for AI-Driven Pan- Cancer Diagnostics
Project Description
Histopathological examination of tumor tissue is the gold standard for the diagnosis of cancer. Recently, molecular pathological assignment of tumor tissue has also become possible by recognizing the methylation patterns of the tumor genome. This involves the identification and classification of tumor entity-specific hyper and hypomethylated promoter regions of oncogenes and tumor suppressor genes. This method has reached application maturity as a diagnostic procedure for both brain tumors and non-brain tumors. Specimen extraction (PE) is usually performed by an invasive surgical procedure. Especially in brain tumors, brain stem or tumor diseases with leptomeningeal spread, this is difficult or not possible due to possible cerebral side effects, unjustifiable risks or lack of solid tumor mass. A so-called »liquid biopsy« (LB), the extraction of cell-free tumor DNA (cftDNA) from plasma or cerebrospinal fluid (CSF) provides an alternative to neurosurgical PE. In this project, for the first time, methylation patterns of cftDNA will be determined from CSF and used to classify brain metastases and differentiate meningeosis neoplastica. This is made possible by the use of innovative technologies such as nanopore sequencing and a cancer classifier based on the machine-learning model random forest. Nanopore sequencing allows a cost-effective and time-efficient reading of the base sequence by voltage changes during the transport of DNA through a nanopore. We have already created a fi rst version of the cancer classifier with public methylation data of brain-derived and some first non-cerebral tumors. The goal is to extend this with further public data up to about 150 additional
tumor entities. This should enable a minimally invasive, cross-organ, methylation-based classification of cancers.Dr. med. Sabine Bélard, MSc, DTM&H
Charité – Universitätsmedizin Berlin, Department of Pediatrics, Division of Pneumonology and Immunology
Email: sabine.belard@charite.de
Fields of Research
- Tuberculosis
- Tropical Medicine
- Infectious Diseases
Project Title
Tuberculous Granuloma Formation, its Biomarkers and Clinical Containment of Tuberculosis Disease
Project Description
Tuberculosis, declared a global public health emergency by the World Health Organization in 1993, remains a major global health concern despite worldwide efforts to increase tuberculosis control and reduce morbidity and mortality. Children are especially vulnerable to develop tuberculosis disease and are at higher risk of severe and disseminated manifestations of tuberculosis. The age-dependency of development and severity of tuberculosis in children has been attributed to immature immune function, which is still ill defined. The tuberculous granuloma is a recognized host-protective hallmark structure of tuberculosis in adults; without effective granuloma formation, pathogen dissemination is pronounced as reflected by poorly formed granulomas and hyper-susceptibility to Mycobacterium tuberculosis under various immune compromising conditions (e.g. HIV). Identifying differences in immune responses between those who control versus those who fail to control tuberculosis infection and disease dissemination is a prerequisite for development of new diagnostic tools to differentiate active from latent tuberculosis and for interventions that will improve immune-mediated protection. This project aims at investigating tuberculous granuloma formation in children to identify biomarkers for clinical control and containment of tuberculosis disease.
Dr. med. Niklas Beyhoff
Charité – Universitätsmedizin Berlin, Department of Cardiology
Email: niklas.beyhoff@charite.de
Fields of Research
- Cardiooncology
- Cardiology
- Cancer
- Lipidomics
Project Title
Lipidomics in Anthracycline-Induced Cardiotoxicity – Identification of Novel Signaling Pathways and Drug Targets
Project Description
Anthracyclines are highly potent cytostatic drugs that are widely used for the treatment of solid tumors (e.g, breast cancer or gastric cancer) as well as various leukemias and lymphomas. Unfortunately, anthracyclines are associated with severe cardiotoxic side effects resulting in dose limitation and substantial long-term complications like the development of congestive heart failure. Although there is good awareness of the potential cardiotoxicity and current guidelines recommend dose limitation in order to prevent those, cardiac damage is evident in more than 20% of patients in current clinical practice. Despite excessive research activities during the last decades, the underlying mechanisms of anthracycline- cardiotoxicity are incompletely understood, and effective strategies for prevention or treatment are currently lacking. There is evidence that anthracyclines lead to changes in cardiac lipid metabolism and that their cardiotoxicity is mediated by generation of reactive oxygen species damaging lipid membranes in cardiomyocytes. Additionally, biophysical studies indicate that anthracyclines can hamper cell function by forming complexes with lipids of the inner mitochondrial membrane. Novel mass spectrometry-based methods allow systematic investigations of the totality of lipids in cells or organs (»lipidomics«), however, data on their application in the context of anthracycline-induced cardiotoxicity is currently lacking. This project aims to characterize the lipidome changes of cardiomyocytes in response to anthracycline treatment. Based upon this, novel signaling pathways, changes in cell metabolism, and (sub-)cellular drug targets will be identified. Ultimately, potential drug candidates will be tested in vitro regarding their ability to prevent/treat anthracycline-induced cardiotoxicity.
Dr. med. Aitomi Bittner
Charité – Universitätsmedizin Berlin, Medical Department, Division of Hematology, Oncology and Tumor Immunology
Email: aitomi.bittner@charite.de
Fields of Research
- Lymphomagenesis
- Personalized Medicine
- Patient‐Derived Xenografts
Project Title
Establishment of a Patient-Specific Syngeneic Immune and Lymphoma PDX-Model for Functional Lymphoma Pathogenesis, Therapy-Prediction and Biomarker-Development
Project Description
Experimental studies in animal models, particularly in transgenic mice models, led to a fundamental under- standing of the functional role of activated oncogenes and inactivated tumor suppressor genes as well as of stress-response-programs as apoptosis or cellular senescence in human lymphoma. However, due to species differences, these models can only recapitulate parts of the temporospatial genetic complexity of human lymphoma pathogenesis. In order to recapitulate human biological systems more closely, sophisticated small-animal models are acutely required. Systemic-orthotope propagation of primary patient-derived tumor-material in immunodeficient mice (so-called »Patient-derived Xenografts [PDX]«) is one solution. These PDX-lymphoma-models are particularly attractive, because a previous transplantation of syngeneic hematopoietic stem and progenitor cells (HPSC) achieves a human-reconstitution of hematopoiesis and immune system, leading to a very extensive humanization of tumor-microenvironment in bone marrow, lymph node, spleen, thymus and peripheral blood. By now, specific profoundly immunodeficient mice are developed. This allows an efficient engraftment of HSPCs with subsequent development of all significant immune cell populations. The general aim of this project is to reconstitute patient-specific syngeneic immune and lymphoma cells in humanized PDX-mice as a clinical relevant test-platform for the investigation of lymphoma-pathogenesis, personalized therapy-response and biomarker-development. A long-term aim of this clinical-translational project is to use this lymphoma-mouse-model for prediction of individual therapy response to one or a combination of new targeted-therapies, biologicals, and antibodies.
Dr. med. Elisabeth Blüthner
Charité – Universitätsmedizin Berlin, Department of Hepatology and Gastroenterology
Email: elisabeth.bluethner@charite.de
Fields of Research
- Intestinal failure
- Intestinal failure-associated liver disease (IFALD)
- GLP-2 analogues
- Amyloidosis
Project Title
Effect of Genetics, Trace Elements and Parenteral Nutrition on Intestinal Failure Associated Liver Disease.
Project Description
Epidemiological data have shown that the incidence of chronic intestinal failure (CIF) is rising and is expected to further increase in the next decades most likely due to complications of more aggressive surgical approaches and improved perioperative management. Parenteral nutrition (PN) remains the mainstay of treatment for CIF but might be associated with potentially life-threatening complications. Intestinal failure associated liver disease (IFALD) is one of the leading long-term complications and causes of deaths in adult CIF patients receiving home parenteral nutrition. Of note, the pathophysiologic mechanisms of IFALD have not been discovered yet and seem to be of multifactorial genesis. However, promising non-invasive liver function tests and new experimental results propose a novel holistic approach to completely understand the aetiology and pathophysiology of IFALD. The aim of this study is a comprehensive analysis of the pathogenesis of hepatic damage in intestinal failure patients receiving parenteral nutrition based on the effect of genetics, serum trace elements and parenteral nutrition. This study will attribute to a greater understanding of the pathogenesis of IFALD and may lead to targeted interventions to prevent and treat the condition (e.g. individual manganese supplements, non-invasive liver assessment in clinical routine workup, development of an accurate predictive score for IFALD).
PD Dr. med. Peter Bobbert
PD Dr. med. Wolfgang Böhmerle
Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology
Email: wolfgang.boehmerle@charite.de
Fields of Research
- Neurotoxicity
- Chemotherapy Induced Neuropathy
- Experimental Neurology
Project Title
Pathophysiology and Prevention of Chemotherapy-Induced Neuropathy
Project Description
Neurotoxic phenomena are among the most common side effects of cytostatic chemotherapy and affect a large number of patients. They further increase the burden of disease for patients and directly affect prognosis by necessitating treatment changes. Despite the high relevance for patients, comparatively little research efforts are allocated to neurological side effects of chemotherapy. In the past, neuroprotective interventions for neurological diseases such as stroke have failed in clinical trials due to the unpredictable onset of damage. In contrast, chemotherapy-induced neurotoxicity is ideally suited for a preventive therapy, as the time point of damage is well defined and evidence suggests that the molecular mechanisms of neurotoxicity differ from the cytostatic mode of action in many chemotherapeutic agents. We hypothesize that an impaired intracellular calcium (Ca2+)
homeostasis is an important aspect of chemotherapy-induced peripheral neuropathy (CIPN) and a potential therapeutic target. In an initial step, we thus established cell- and animal models of chemotherapy-induced neuropathy for a number of clinically relevant cytostatic drugs. These models are then used to further elucidate the role of a deranged intracellular Ca2+ homeostasis in CIPN. In addition to this line of experiments, we use a screen of differentially regulated miRNAs to identify novel disease mechanisms. Understanding the molecular mechanisms underlying CIPN development will not only improve our understanding for the (patho-)physiological states of sensory neurons, but also enable us to develop new strategies for the prevention and treatment of CIPN.Dr. med. Friederike Borngräber
Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology
Email: friederike.borngraeber@charite.de
Fields of Research
- Musician’s Dystonia
- Electrical Cerebellar Stimulation
Project Title
Characterization of Cerebellar Function in Musician’s Dystonia Patients and its Electrical Modulation Capability
Project Description
Musician’s dystonia (MD) is a task-specific form of focal dystonia that manifests itself as a loss of voluntary mo- tor control when playing an instrument. Up to 1-2% of professional musicians are affected, and in many cases, the disorder terminates the professional career. The underlying pathophysiology is not fully understood. How- ever, recent findings suggest a cerebellar contribution to the disease. For instance, cerebellar activity is reduced in other forms of isolated dystonia like cervical dystonia leading to an abnormal excitability of the cortex. Therefore, the study aims at investigating the cerebellar influence to the pathomechanism of MD. We hypothesize that reinforcement of the cerebellar output will lead to a clinical improvement of symptoms. In order to modulate the cerebellar activity, we will apply oscillating transcranial direct current (o-tDCS), alternating current (tACS) and placebo stimulation to the cerebellum on three different days. A cohort of 15 pianists with focal hand dystonia will be compared to a control group of 15 healthy pianists to take in to account sensorimotor adaptation due to prior musical training. Electroencephalographical measurements before and after the intervention will help to explore the stimulations’ effect on differ- ent frequency bands of the cortex. Clinical outcome will be measured via MIDI recordings of the piano playing, scor- ing parameters like the variability of inter-onset intervals, velocity and error rate. The findings of this study may have considerable consequences for the therapeutic treatment of MD patients.
Marie Bossen
Charité - Universitätsmedizin Berlin, Charité Comprehensive Cancer Center (CCM)
Email: marie.bossen@charite.de
Fields of Research
- precision oncology
- preclinical cancer models
- tumor microenvironment
Project Title
Establishment of representative 3D model systems of metastatic colon cancer for rapid pharmacotyping
Project Description
Despite early diagnosis through the widespread use of screening strategies and improved treatment regimens, colorectal cancer (CRC) still represents the second most common cause of cancer-related mortality. Especially the metastatic stage (mCRC), in which nearly a quarter of patients are diagnosed, is characterized by a dismal prognosis. Thus, mCRC remains a major clinical challenge that makes the development of clinically relevant in vitro models for preclinical drug testing and guidance of personalized treatment approaches crucial to improve patient’s survival rates.
The aim of our research project is to develop representative model systems that reliably reflect the biology and complexity of mCRC in order to increase the successful translation of in vitro results into clinical practice. Therefore, three different patientderived 3D model systems of mCRC are established and compared to the original tumors in terms of their cellular composition and molecular characteristics by performing cell stainings and multi-omics approaches (mutational profiling, proteomics). To allow clinical implementation, the preclinical drug testing procedure is optimized to reduce the time span between sample collection and the report of drug sensitivity.Univ.-Prof. Dr. med. Elena Ioana Braicu, MSc
PD Dr. med. Tim Bastian Brämswig
Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology
Email: tim‐bastian.braemswig@charite.de
Fields of Research
- Silent Brain Infarcts
- Cerebral Imaging in Stroke
- Stroke
Project Title
Sonolysis in Prevention of Silent Brain Infarction During Transcatheter Mitral Valve Repair with the MitraClip-System
Project Description
Silent cerebrovascular disease is the most commonly detected incidental finding on brain imaging. Although called silent, these brain lesions are associated with subtle deficits (e.g. cognitive and motor deficits, gait impairment, impairments in activities of living). Further-more, risk of future overt strokes and dementia is increased in patients with silent cerebrovascular disease (Smith et al., 2017).
In this project, we assessed the occurrence and clinical significance of covert brain infarction and cerebral microbleeds (two cardinal manifestations of silent cere-brovascular disease) in different study populations with cardiovascular diseases (i.a., Braemswig et al. 2022 & 2023). Further, in cooperation with the Department of Cardiology, we are investigating whether sonolysis (con-tinuous transcranial Doppler monitoring) reduces the risk of covert brain infarction during transcatheter edge-to-edge repair of the mitral valve.Dr. med. Tim Bastian Brämswig
Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology
Email: tim‐bastian.braemswig@charite.de
Fields of Research
- Silent Brain Infarcts
- Cerebral Imaging in Stroke
Project Title
Silent Brain Infarcts – Incidental Finding or Risk Factor?
Project Description
Ischemic brain lesions in cerebral imaging without a matching clinical syndrome are described as silent brain infarcts. Silent brain infarcts appear frequently in the general population and are associated with future strokes and dementia. Others and we have reported that subsequent new diffusion-weighted imaging (DWI) lesions on magnetic resonance imaging (MRI) are also common in patients with a clinically manifest acute ischemic stroke. In our study, new DWI lesions were detected in 38% of the study population within one week after the initial ischemic event. Clinical stroke recurrence occurred in only 2%. Thus, most of the new DWI lesions appeared clinically silent (Braemswig et al, Stroke 2013). Additionally, patients with elevated glycated hemoglobin (HbA1c) were found to have an increased risk for new, de novo DWI lesions in the acute phase after an ischemic stroke (Braemswig et al., Front. Neurol. 2017). Silent brain infarcts appear often during certain operative and interventional procedures. In cooperation with the Department of Cardiology, we want to describe frequency and distribution of new DWI lesions on MRI following Mitra- Clip procedure. Besides, we perform continuous transcranial Doppler ultrasonography (TCD) during MitraClip procedure to detect microembolic signals (MES) and to allocate MES to specific phases of the procedure.
PD Dr. med. Eva Janina Brandl
Charité – Universitätsmedizin Berlin, Department of Psychiatry and Psychotherapy
Email: eva.brandl@charite.de
Fields of Research
- Psychiatric Pharmacogenetics
- Transcultural Psychiatry
- Peripartum Psychiatric Disorders
Project Title
Psychosocial and Genetic Factors Influencing Antidepressant Response in Patients of Turkish Origin
Project Description
Genetic factors are known to influence the risk for psychiatric disorders as well response to psychopharmacological treatment (e.g., Brandl et al., 2014, Lett et al., 2016). However, only few findings have yielded independent replication, and pharmacogenetic testing has not yet been successfully established in clinical practice (Müller/Brandl et al., 2018). Further research is required to achieve a more detailed understanding of genetic underpinnings of treatment response. In particular, the interaction between genetic and psychosocial factors influencing treatment response is poorly understood. Moreover, there are a number of ethnic groups where pharmacogenetic factors have not been studied sufficiently in psychiatric research. Therefore, this research project investigates psychosocial as well as pharmacogenetic influences on antidepressant response in patients of Turkish origin. Migrants with Turkish background have a high risk for development of depression and other psychiatric disorders. They show a high symptom load and more often receive polypharmacy (Brandl et al., 2018), reflecting poorer treatment response compared to patients without migration background. However, there is only sparse literature on psychosocial factors influencing antidepressant treatment response in migrants in general as well as on pharmacogenetics of antidepressant response in patients of Turkish origin. The project investigates antidepressant response in patients of Turkish origin with major depression over the first eight weeks of treatment and aims to identify psychosocial as well as genetic factors associated with treatment response. The results of the project will not only contribute to pharmacogenetic research but may also help to improve psychiatric treatment for this underserved population in the future.
Dr. med. Katarina Braune
Charité – Universitätsmedizin Berlin, Department of Pediatrics, Division of Endocrinology and Diabetology
Email: katarina.braune@charite.de
Fields of Research
- Telemedicine
- Big Data
- Value‐Based Health Care
Project Title
Digital Diabetes Clinic (DDC) – A Pioneer Project in Value-Based Health Care
Project Description
Diabetes represents a growing challenge for health systems everywhere. Its prevalence has been continuously growing over the last decades, with the financial and human burden on health care systems increasing as a result. For children and adolescents living with diabetes, innovative treatment options involving insulin pumps and continuous glucose monitoring systems are available today. However, to benefit the most from the use of these tools, a high level of patient empowerment and self-care is essential. Furthermore, a higher level of digitalization in the respective hospital is required. Without appropriate tools for data collection and analysis, a vast amount of useful patient data does not get assessed and is therefore lost potential for better patient outcomes. We have experienced that conventional visits in our diabetes outpatient clinic and inpatient admissions to our hospital ward put our patients in an artificial time window. Rarely do they represent daily challenges and actual needs of our patients. A paradigm shift is needed in how health services are delivered, managed, and funded. Integrated Care Pathways (ICPs) are one of the current most promising strategies with a novel approach to mutual-decision making and organization of care. ICPs are personalized, structured multidisciplinary care plans aiming to enhance health-related quality of life by improving patient outcomes, promoting patient safety, increasing patient satisfaction, and optimizing the use of resources. From a patient’s perspective, integrated care aims to meet their health and social needs, taking these as a starting point for redesigning their care. This project aims to investigate quality of care (patient outcomes, patient and health care professional satisfaction) using an integrated platform for patient data assessment and performing mobile clinic visits through telemedicine as a first step of a new ICP plan. Furthermore, we intend to analyse success factors and barriers for our Paediatric Diabetes Unit on its way from conventional care to a digital clinic. With this novel approach in Paediatric diabetes care, we hope to serve as a lighthouse project for management plans for more chronic diseases in Paediatric and Adult Care of the Charité – Universitätsmedizin Berlin, as well as for Paediatric and Adult Diabetes Centres worldwide.
Georg Braune
Charité - Universitätsmedizin Berlin, Institut für Biochemie und Molekularbiologie (CCM)
Email: georg.braune@charite.de
Fields of Research
- Developmental Biology
- Neurology
- Organoid Research
Project Title
Notch3-dependent control of Neural Stem Cells behavior in a human iPSCs-derived cerebral organoids model of CADASIL
Project Description
The nervous system is in many ways the most complex tissue in an organism. It contains many different cell types that with their interactions build a network out of which emerge our thoughts, feelings and our personality. The process of the development and maintenance of this system is called neurogenesis. It is orchestrated by the interplay of many different signaling pathways both during embryonal development and adulthood. One of them is the Notch3 signaling pathway that was shown in zebrafish and mice to have a high importance in maintaining neural stem cell quiescence in the adult brain (Alunni et al., 2013, Kawai at al., 2017). The involvement of Notch3 in human neurogenesis is yet to be discovered.
In humans, mutations in Notch3 lead to the CADASIL syndrome, a yet incurable disease representing the most common inheritable cause of strokes (Chabriat et. Al, 2009). Besides that, CADASIL patients show progressive cognitive decline ultimately leading to severe dementia. Given the fact that Notch3 is known to regulate vascular smooth muscle cell function and maturation of arteries (Wang et al., 2007) and considering the vascular occlusions observable in the brains of affected patients, CADASIL is currently classified as a disease of the vasculature with neuronal defects considered to be a secondary consequence. However sometimes cognitive decline occurs before vascular occlusions (Amberla et al., 2004) and considering the importance of Notch3 in
regulating neurogenesis in other organisms we hypothesize a primary neuronal phenotype in CADASIL syndrome that is independent of vascular impairments.
Here we use cerebral organoids as a vasculature-free model to investigate the role of Notch3 during human neurogenesis (Lancaster et al., 2013). To do so we generate cerebral organoids from induced pluripotent stem cells (iPSCs) derived from skin fibroblasts from patients with the CADASIL syndrome and from iPSCs with a full Notch3 knockout. In these organoids we will quantify stem cell fate choices by combining markers of different progenitor populations with BrdU-lineage tracing.Dr. med. Katarina Braune
Charité – Universitätsmedizin Berlin, Department of Pediatrics, Division of Endocrinology and Diabetology
Email: katarina.braune@charite.de
Fields of Research
- Telemedicine
- Big Data
- Value‐Based Health Care
Project Title
Digital Diabetes Clinic (DDC) – A Pioneer Project in Value-Based Health Care
Project Description
Diabetes represents a growing challenge for health systems everywhere. Its prevalence has been continuously growing over the last decades, with the financial and human burden on health care systems increasing as a result. For children and adolescents living with diabetes, innovative treatment options involving insulin pumps and continuous glucose monitoring systems are available today. However, to benefit the most from the use of these tools, a high level of patient empowerment and self-care is essential. Furthermore, a higher level of digitalization in the respective hospital is required. Without appropriate tools for data collection and analysis, a vast amount of useful patient data does not get assessed and is therefore lost potential for better patient outcomes. We have experienced that conventional visits in our diabetes outpatient clinic and inpatient admissions to our hospital ward put our patients in an artificial time window. Rarely do they represent daily challenges and actual needs of our patients. A paradigm shift is needed in how health services are delivered, managed, and funded. Integrated Care Pathways (ICPs) are one of the current most promising strategies with a novel approach to mutual-decision making and organization of care. ICPs are personalized, structured multidisciplinary care plans aiming to enhance health-related quality of life by improving patient outcomes, promoting patient safety, increasing patient satisfaction, and optimizing the use of resources. From a patient’s perspective, integrated care aims to meet their health and social needs, taking these as a starting point for redesigning their care. This project aims to investigate quality of care (patient outcomes, patient and health care professional satisfaction) using an integrated platform for patient data assessment and performing mobile clinic visits through telemedicine as a first step of a new ICP plan. Furthermore, we intend to analyse success factors and barriers for our Paediatric Diabetes Unit on its way from conventional care to a digital clinic. With this novel approach in Paediatric diabetes care, we hope to serve as a lighthouse project for management plans for more chronic diseases in Paediatric and Adult Care of the Charité – Universitätsmedizin Berlin, as well as for Paediatric and Adult Diabetes Centres worldwide.
PD Dr. med. Tobias Brockmann, FEBO
Charité – Universitätsmedizin Berlin, Department of Ophthalmology
Email: tobias.brockmann@charite.de
Fields of Research
- Wound Healing and Fibrogenesis
- Complement System and Inflammation
- Cornea and Ocular Anterior Segment
Project Title
Influence of the Complement System on the Myofibroblast Activation During Corneal Wound Healing
Project Description
Degenerative eye disorders, which are associated to a severe loss of visual acuity very often are the result of misguided angiogenesis or wound healing/fibrogenesis; and thereby are the response to ischemic of inflammatory processes. Today, there are no causal therapeutic approaches for the treatment of fibrotic eye disorders. Hence, the aim of my BIH Charité Clinician Scientist project is to investigate the Influence of the complement system on the myofibroblast activation during corneal
wound healing. Therefore, we will analyze molecular mechanisms of human specimens and perform animal experiments to identify involved key processes. Thereby we will contribute to a better understanding of fundamental pathomechanisms of corneal wound healing. Finally, current treatment regimes shall be optimized and new therapeutic approaches may be derived.PD Dr. med. Claudia Brockmann, FEBO
Charité – Universitätsmedizin Berlin, Department of Ophthalmology
Email: claudia.brockmann@charite.de
Fields of Research
- Retinal Angiogenesis
- Retinal Neurodegeneration
- Hereditary Retinal Dystrophy
Project Title
Interaction Between Pathological Angiogenesis and Retinal Neurodegeneration
Project Description
In recent years, treatment and prevention of vascular retinal diseases has decisively improved, in particular with regard to age-related macular degeneration, diabetic and veno-occlusive retinopathy. Nevertheless, current firstline therapy with inhibition of the vascular endothelial growth factor (VEGF) is limited. Pathological vessel growth can be inhibited as long as continuous intravitreal anti VEGF injections are given, however, in long-term use it causes irreversible retinal ischemia and atrophy. Based on this background, detailed interaction between inhibition of pathological angiogenesis and retinal neurodegeneration is poorly understood. The aim of my research project is to analyze the interaction between pathological angiogenesis and retinal neurodegeneration. Using animal experimental approaches molecular mechanisms of mutual influences will be investigated. Furthermore, pathological processes of vascular and primary neurodegenerative retinal diseases will be compared. Thereby fundamental pathomechanisms of degenerative retinal diseases should be better understood to develop novel treatment strategies. Finally, results obtained should be compared with outcome of clinical studies.
PD Dr. med. Catharina Busch
PD Dr. med. Federico Collettini
Charité – Universitätsmedizin Berlin, Department of Radiology (including Pediatric Radiology)
Email: federico.collettini@charite.de
Fields of Research
- Image‐Guided Ablative Tumor Therapy
Project Title
Beyond the Margin of Local Ablation: Perifocal Immune Responseand Tumor Progression After Image-Guided Ablative Tumor Therapies in a VX2 Liver Tumor Model
Project Description
While surgery remains the favored treatment option for resectable liver malignancies, only a minority of patients is amenable to surgery at presentation. This situation has led to the development of various minimally invasive tumor ablation techniques for patients with unresectable liver tumors. The most commonly used and best-under- stood ablative technique is radiofrequency ablation (RFA), which has now been officially included into international treatment guidelines and, since 2012, has been the therapy of choice in patients with very early hepatocellular carcinoma not amenable to liver transplantation. The underlying tumoricidal effect of RFA relies on the generation of frictional heat, which results in thermal coagulation necrosis of the tumor and the surrounding peritumoral tissue. However, only limited knowledge is available on the perifocal ablation zone beyond the ablation margin and immune response observed after image-guided tumor therapy. Initial evidence suggests that perifocally expressed immunomodulators have a role in tumor progression following local ablation. Hence, the overall goal of our project is to characterize the tissue rim surrounding the ablation zone following use of different ablative modalities and to elucidate the effects of local ablation on residual tumor deposits and systemic spread in a VX2 liver tumor model.
PD Dr. med. Marcus Czabanka
Prof. Dr. med. Frederik Damm
Charité – Universitätsmedizin Berlin, Medical Department, Division of Hematology, Oncology and Tumor Immunology
Email: frederik.damm@charite.de
Fields of Research
- Hematopoietic Stem Cells
- Clonal Hematopoiesis and Preleukemia
- Lymphomagenesis
Project Title
Molecular Characterization of Hematopoietic Stem and Progenitor Cell Involvement During Leukemo- and Lymphomagenesis
Project Description
The hematopoietic system is organized as cell hierarchy having at its top, a hematopoietic stem cell (HSC) and organized in three cell compartments, the hematopoietic stem cells compartment, the progenitor compartment and the mature cells compartment. The hematopoietic stem cell functions are tightly regulated by a specific microenvironment mainly located in the bone marrow for the HSC, but other microenvironments are involved in the differentiation of lymphoid progenitors such as the thymus for early T cell differentiation. Leukemia (or lymphoma) development results from the accumulation of mutations, generally somatic. We and others have reported that acquired mutations affecting early progenitors occur in various myeloid malignancies such as acute myeloid leukemia, or myelodysplastic syndromes. However, the contribution of progenitors to lymphomagenesis is less understood. We investigated the repartition of acquired mutations in the hematopoietic differentiation tree of chronic lymphocytic leukemia (CLL) patients. Our findings establish the presence of acquired mutations in multipotent hematopoietic progenitors and show that CLL develop from a pre-leukemic phase and propose abnormality in hematopoietic and early B-cell differentiation through deregulation of the MAP kinase pathway as a paradigm for the initial steps of CLL development (Damm et al., Cancer Discovery 2014). In order to gain further insights into the role of progenitor involvement of different lymphoid malignancies, we investigate patients suffering from various types of lymphomas, using a combination of whole-exome and targeted deep resequencing. We study the ontogeny, clonal hierarchy, their dynamics and evolution during the clinical course. To this aim, flow-sorted cell fractions, single cells, and different compartments are analyzed.
Dr. med. Natasha Darcy
Email: natasha.darcy@charite.de
Fields of Research
- Movement Disorders
- Genetic Parkinson's Disease
- Deep Brain Stimulation
Project Title
Elektrophysiologische Merkmale der genetischen versus sporadischen Parkinson-Erkrankung anhand von Tiefenableitungen
Project Description
Research into the genetic basis of neurodegenerative diseases is expanding as the potential for preventative or curative measures to combat these widespread and debilitating progressive diseases is recognised. In Parkinson’s disease (PD), the past three decades have produced more than twenty genetic variants associated with a higher risk for developing the disease, often at a younger age and sometimes with characteristic disease course.
In deep brain stimulation (DBS), an increasingly common treatment for medically resistant PD, electrodes are implanted into the basal ganglia, most often the subthalamic nucleus (STN). By applying electrical current, DBS is effective at modulating the pathological network activity and improving symptoms. Conversely, it allows unprecedented insights into subcortical brain activity by measuring so-called local field potentials around the electrodes. Pathologically synchronised activity in the beta frequency range (13-30 Hz) measured by these electrodes is known to correlate with symptom load. To this day, it remains unclear how exactly this reflects the pathology of PD, at which stage in disease progression it appears and where it falls on the spectrum of hallmark to epiphenomenon of disease pathology.
Research into genetic PD, including whether beta activity is present in these types has important consequences for both pathophysiological understanding and for treatment options regarding DBS and, more specifically, adaptive DBS. Still in development, current strategy often relies on STN beta-activity as the physiomarker for triggering stimulation. For patients with genetic PD, who are often younger at disease onset and stand to profit from the advantages, namely reduction of side effects and sparing of battery life, it is therefore crucial to discover whether this marker is reliable. With the time allocated to me by the Junior Clinician Scientist program, I aim to gather both retrospective and prospective deep brain recordings from genetic and sporadic PD patients undergoing STN-DBS in order to compare the electrophysiological profiles and most notably the presence or absence of characteristically enhanced beta activity.
This research will facilitate pathophysiological understanding of this physiomarker and be an important guide to patients with genetic Parkinson's disease considering treatment with deep brain stimulation.Dr. med. Anja-Maria Davids
Dr. med. Ana Luisa de Almeida Marcellino
Charité – Universitätsmedizin Berlin, Department of Neurology and Experimental Neurology
Email: ana.almeida@charite.de
Fields of Research
- Cerebral palsy
- Functional connectivity
- Deep brain stimulation
Project Title
Functional Networks of Dyskinetic Cerebral Palsy: a Lesion-Based Study
Project Description
Infantile cerebral palsy is a broad term for pre- or perinatally acquired, non-progressive, predominantly motor disorders that can affect muscle tone, strength and/or posture. The dyskinetic subtype represents 10-14% of all cases and is characterised by the presence of complex hyperkinetic movement disorders including dystonia and choreoathetosis. Current treatment is solely symptomatic and largely unsatisfactory. Dyskinetic cerebral palsy (dCP) is associated with lesions in the basal ganglia, thalamus and cerebellum. To what extent lesion characteristics such as specific location or functional connectivity are associated with clinical movement disorder patterns is still not clear. Deep brain stimulation (DBS) is an established treatment for Parkinson’s disease or primary dystonia and is known to modulate abnormal motor network activity. In contrast to primary dystonia, DBS of the globus pallidus internus for patients with dCP has shown heterogeneous results. Understanding which functional networks underlie specific movement disorder patterns in dCP might facilitate patient and target selection for neuromodulatory treatments such as DBS. In this study, we hypothesise that different clinical movement disorder patterns (e.g. predominant dystonia or chorea) in dCP are related to lesions in specific nodes of larger functionally connected networks. To test this hypothesis, 30 patients with dCP will undergo a thorough clinical examination aimed at characterising the clinical movement disorder pattern. In a second step, cranial MRIs of included patients will be analysed and existing lesions delineated in order to investigate their association with the individual movement disorder. Lastly, perturbed functional networks underlying different movement disorder patterns in patients with dCP will be identified using lesion network mapping. On the longterm, these findings could be used to explore targeted treatments for dCP, taking into account individual clinical phenotypes of this heterogeneous disease entity.
Dr. med. Fabian Dirks
Dr. rer. nat. Jan Rafael Dörr
Charité – Universitätsmedizin Berlin, Department of Pediatric Oncology and Hematology
Email: jan-rafael.doerr@charite.de
Fields of Research
- Cancer
- Senescence
- Cancer Immunotherapy
Project Title
Development of Minimal Invasive Diagnostic Tools and Targeted Therapies for Tumor Cell Senescence
Project Description
Despite our rapidly expanding knowledge of cancer genomes and their mutational landscapes, the functional understanding of cellular failsafe programs, which prohibit cancer development and which underly cancer treatment principles, remains incomplete. Alongside apoptosis premature senescence represents a major cellular failsafe mechanism in both mice and men, since it induces a terminal proliferation arrest of viable tumor cells. In this way senescence controls tumor growth as part of cytotoxic therapies. Although therapy-induced senescence (TIS) can prolong tumor-free survival and improve treatment outcome, senescent tumor cells also acquire harmful characteristics: They display an increased stemness potential and persistently remodel their tissue environment predominantly through their enhanced secretory activity. In this way senescence contributes to treatment resistence. However, diagnostic tools, which faithfully detect TIS in the clinic and which could subsequently guide treatment decisions, are largely missing. Moreover, the targeted elimination of senescent tumor cells presents a weakly explored therapeutic opportunity. In the Clinician Scientist Program I therefore aim to elucidate senescence-induced modifications of the tumor stroma and the immune system predominantly in mouse lymphoma as well as neuroblastoma models with the goal to develop minimal invasive senescence screens and to explore novel senescence treatment strategies.
Dr. med. Mihnea-Paul Dragomir
Email: mihnea.dragomir@charite.de
Fields of Research
- Tumors of the ovary
- Mucinous tumors
- DNA methylation
Project Title
Using DNA methylation profiling for differential diagnosis and for determining the origin of ovarian mucinous carcinomas
Project Description
Primary mucinous ovarian carcinoma (PMOC) is a rare subtype of ovarian cancer with an unfavorable outcome. It is estimated that POMC account for 3 to 4% of all primary ovarian carcinomas. PMOCs, if not diagnosed at an early stage have an unfavorable response to chemo- and radiotherapy and most patients with extra-ovarian involvement die of the disease. The ovary is also the site of frequent metastases of other mucinous tumors. These tumors are termed secondary mucinous ovarian carcinoma (SMOC) and account for approximately 10% of the malignant neoplasms of the ovary. SMOCs originate from diverse extra-ovarian sites such as the stomach, the colon, the appendix, the pancreas, and the uterus. The histopathological differentiation of PMOC from SMOC is difficult and represents an unmet medical need. Current clinical practice differential diagnosis is rudimentary and is based on clinical features, histopathology and immunohistochemistry. Hence, in order to distinguish PMOC from SMOC in a reliable and rapid way, new diagnostic tools need to be developed which improve current methods. Additionally, it is important to mention that often SMOCs are identified without knowing the location of the primary.
DNA methylation patterns are highly tissue specific, hence are an ideal method for performing differential diagnosis of POMC versus SMOC. Hence, my aim is to use DNA methylation profiling to develop machine learning algorithms for differential diagnosis of PMOC from SMOC, and that are able to indicate the tissue of origin of SMOCs.
This can lead to the development of a new technology that addresses an unmet medical need – the timely and precise diagnosis of mucinous carcinoma of the ovary. It is important to emphasize that the current diagnosis for these tumors is slow, delaying the therapy and unprecise. According to most international guidelines, the first line of therapy should be based on the tissue of origin, hence a precise differential diagnosis is essential.Dr. med. Sophie Lan-Linh Duong
Charité – Universitätsmedizin Berlin, Department of Neurology and Experimental Neurology
Email: sophie.duong@charite.de
Fields of Research
- Neuroscience
- Neuroimmunology
- Autoimmune Encephalitis
Project Title
Characterization of patient-derived IgLON5 monoclonal antibody pathogenicity in anti-IgLON5 disease
Project Description
Anti-IgLON5 disease is a progressive neurological disorder presenting with multifaceted sleep and movement disorders, cognitive impairment, and bulbar dysfunction that can progress to respiratory failure and death. What is unique about anti-IgLON5 disease is that it shares features of both neuronal autoimmunity and neurodegeneration. While the presence of antibodies against the surface antigen IgLON5 suggests neuroinflammation, the detection of hyperphosphorylated tau and neuronal loss, proposes a neurodegenerative tauopathy. Whether IgLON5 antibodies primarily induce neurodegeneration or rather present a sequalae of the neurodegenerative processes needs to be solved. Previous studies with polyclonal serum and cerebrospinal fluid (CSF) from patients suggest a down-regulation of IgLON5 protein and disruption of the neurofilament architecture in cultured neurons. However, it is unclear whether the observed structural and functional effects exclusively relate to IgLON5 antibodies or are confounded by the presence of other clinically relevant autoantibodies in the polyclonal patient sample. Studies are necessary for detailed insights into the antibody repertoire of patients with anti-IgLON5 disease and the potential disease-driving pathogenic effects of IgLON5 antibodies. Using established methods in the recombinant generation of disease-specific monoclonal antibodies (mAbs) from patients’ CSF or serum, this project aims to characterize the pathogenic mechanisms underlying anti-IgLON5 disease. These patient-derived mAbs will allow the detailed and systematic characterization of the functional role of IgLON5 antibodies, thereby specifically addressing the following questions: 1. From where do pathogenic IgLON5 antibodies originate? 2. Are CSF-derived IgLON5 antibodies pathogenic? 3. Are IgLON5 mAbs the primary drivers of neurodegeneration in anti-IgLON5 disease? Evidence of antibody pathogenicity in anti-IgLON5 disease will provide the rationale for immunomodulatory measures and enable the development of highly specific antibody-selective immunotherapies, potentially improving patient outcome as most patients remain refractory to the current therapeutic measures that comprise unspecific immunotherapies. Further, this study will foster the understanding of neuroinflammation at the pivot of neurodegeneration with implications extending to post-stroke dementia or cognitive impairment in patients with cancer-associated autoantibodies.
Dr. med. Omar Dzaye, PhD
Charité – Universitätsmedizin Berlin, Department of Radiology
Email: omar.dzaye@charite.de
Fields of Research
- Neuroradiology
- Immunotherapy
- Tumor Metabolism
Project Title
Heterogeneity of Immune Infiltration in Glioblastoma and its Implications for Neuroradiological Diagnosis Based Personalized Treatment Decisions
Project Description
Dr. Dzaye comanages the Cellular Neurosciences Re- search laboratory and is the initiator of the Exchange Program in collaboration with the Johns Hopkins University School of Medicine. Dr. Dzaye works on the development of novel imaging biomarkers, brain tumor response-criteria, staging systems and molecular imaging techniques in brain cancer therapies. His translational research portfolio includes the characterization of novel agents as well as the application of artificial intelligence and machine learning solutions for the assessment of brain cancer. His basic research interest mainly focuses on tumor metabolism and immunooncology: Dr. Dzaye and colleagues have found that microglial cells strongly promote glioma growth and invasion. Versican an endogenous ligand for Toll-like receptors (TLR) is released from glioma and activates TLR2 toll-like receptors in the surrounding GAMs. TLR2 signaling triggers the expression of MT1-MMP and the release of MMP-9 in GAMs and this microglial activity promotes glioma growth. Thus, glioma cells exploit GAMs to promote their invasion. Thus interfering with TLR receptors or their intracellular path- ways reduced the rapid expansion of glioma cells as they could show with TLR2 interfering antibodies and microg- lia cells have become a new target for glioma research and for potential therapy. Creating innovative and clinically practicable solutions and translating them from concept to practice has been Dr. Dzaye central mission for the past seven years.
PD Dr. med. Nadja Ehmke
Charité – Universitätsmedizin Berlin, Institute of Medical Genetics and Human Genetics
Email: nadja.ehmke@charite.de
Fields of Research
- Skeletal Dysplasias
- Bone Development
- Inborn Errors of Metabolism
Project Title
Functional Characterization of the Protein TGDS and the Pathophysiology of Catel-Manzke Syndrome
Project Description
Rare monogenetic skeletal malformations and connective tissue diseases are models for the development and metabolism of the skeleton and connective tissue. The underlying genetic alteration of a large number of such diseases is unknown at the present time, although knowledge of the genetic cause is of great importance to affected families. Catel-Manzke syndrome is an autosomal recessive skeletal disorder, characterized by retrognathia and cleft palate (Pierre-Robin sequence), heart defect, short stature and a unique hand malformation with a bi- lateral deviation of the index fingers. Recently we identified mutations in the gene TGDS as the cause of Catel-Manzke syndrome. We assume a role of the protein TGDS in proteoglycan synthesis or turnover since overlapping skeletal disorders are due to alterations in these processes and TGDS shows similarities to an enzyme involved in proteoglycan synthesis. This project aims to characterize the molecular function of TGDS and the pathomechanism of the disease. Using CRISPR/Cas, a mouse model will be generated and analyzed with cell and molecular biology as well as histological methods. In addition, we intend to use genome sequencing to identify the so far unknown molecular basis of skeletal disorders similar to Catel-Manzke syndrome (»Catel-Manzke-like syndrome«). We expect our results to reveal new aspects of limb, heart and craniofacial bone development and expand the understanding of proteoglycan metabolism, which is involved in a large number of development and aging processes by modulation of various pathways. In addition, we aim to improve the genetic counseling and clinical care of the affected patients and their families.
PD Dr. med. Felix Ehret
Email: felix.ehret@charite.de
Fields of Research
- Translational Neuro-Oncology
- Cancer Epigenetics
- Image-guided Robotic Radiosurgery
Project Title
The Role of Radiotherapy in the Treatment of Atypical Meningiomas – A Methylome- and Genome-based Analysis
Project Description
Meningiomas are the most common intracranial tumors of the central nervous system (CNS). With the revised WHO classification of tumors of the CNS in 2016, molecular markers were introduced to further specify and distinguish certain tumor subtypes. The diagnosis of meningiomas, however, is still solely based on histopathological features. Recently, DNA-methylation-based classifiers have shown to accurately predict and stratify CNS tumors to improve the standardization of tumor diagnostics. The traditional approach of meningioma diagnosis using only light microscopy and immunohistochemistry to distinguish the current fifteen subclasses is prone to interobserver biases and limited regarding risk stratification and personalized treatment decision making. With approximately 80% of meningiomas showing benign behavior (WHO grade I) and a favorable outcome after surgical resection, the remaining 20% tend to recur due to their aggressive histopathological characteristics (WHO grade II and III). In case of atypical meningiomas (WHO grade II), it is still unknown whether and to which degree an adjuvant radiotherapy after surgical resection is required. This knowledge gap is highlighted by various contradictory findings in recent studies and reviews, which were partly conducted at our institution. A recent study established and validated a DNA-methylation-based classifier for meningiomas. Results revealed two distinct molecular subgroups for the atypical meningioma (intermediate-A and -B). Moreover, it was shown that large proportions of transitional meningiomas (WHO grade I) and anaplastic meningiomas (WHO grade III) could be molecularly reclassified into the two new intermediate meningioma classes. Finally, the established DNA-methylation-based classification outperformed the WHO classification concerning clinical outcome prediction. These findings suggest that previous studies of atypical meningiomas may have investigated rather heterogeneous cohorts, including other meningioma subtypes, leading to undetected biases. Ultimately, this risk of bias can only be avoided by implementing a DNA-methylation-based classifier to ensure accurate tumor subtype identification. The role of radiotherapy for atypical meningiomas can be specifically and correctly assessed by doing this. Identifying potential subsets of tumors that profit from radiotherapy is the primary objective of this project and a major goal to avoid over- and undertreatment.
Dr. med. Julius Emmrich, MPhil
Dr. med. Leif-Christopher Engel
PD Dr. med Cornelius Engelmann
Charité – Universitätsmedizin Berlin, Department of Hepatology and Gastroenterology
Email: cornelius.engelmann@charite.de
Fields of Research
- Acute-on-chronic liver failure
- Regeneration
- Senescence
- Cell-Cell interactions mediating organ injury
Project Title
Exploring the Impact of Hepatocyte Senescence on Tissue Injury and Regeneration in Acute-on-Chronic Liver Failure
Project Description
The acute-on-chronic liver failure (ACLF) is a complex disease with devastating prognosis which develops on the basis of an acute decompensated liver cirrhosis in combination with extrahepatic organ failures. Sudden disease worsening is frequently triggered by bacterial infections or other precipitating events which are known to be more harmful when liver cirrhosis is present but easy to handle in patients without liver disease. This observation suggests an organ sensitisation of the liver being the initiating mechanism for ACLF. In addition, a general lack of tissue regeneration was also linked to patients’ persistent organ dysfunction and poor prognosis. Upon injury hepatocytes may develop a cell cycle arrest, so called cellular senescence, which has the potential to explain both observations. Cellular senescence alters the phenotype and receptor expression of hepatocytes and the ability to proliferate and to replace injured tissue. The main aim of that project will be to explore the mechanistic role of hepatocellular senescence in modulating the course of ACFL and severity. As a first step human liver tissue from patients with different severity grades of end-stage liver disease will be characterised for the expression and activation of regenerative and senescent pathways. Focus will be on the Mdm2-p53 pathway, which is the best-described senescence pathway. TLR4 signalling may triggers senescence and we hypothesis that this is mediated by TGF-β1 which trans-activates the p53 pathway independent of DNA damage or other forms of cellular injury. For both objectives the effect of targeted molecule silencing in vitro (e.g. siRNA) and in vivo (e.g. conditional knockout mice) allows to delineate the relevance of senescence pathways in ACLF. Furthermore we are planning to develop a liver ACLF organoid model to mimic part of the complexity of ACLF in vitro. It will allow to pre-test multiple therapeutic compounds to select those with high likelihood for in vivo efficacy. The last objective will be to test pre-se-lected senolytic therapies in different ACLF mouse mod-els and to select the most effective agent for translation into humans. Therefore, this project will combine basic with translational science to understand the mechanism of regenerative response in ACLF, to develop new experimental techniques and also to pave the way for a novel treatment for a disease with still devastating prognosis.
PD Dr. med. Philipp Enghard
Charité – Universitätsmedizin Berlin, Department of Nephrology and Medical Intensive Care
Email: philipp.enghard@charite.de
Fields of Research
- Nephrology
- Immunology
- T cells
Project Title
Cellular Urinomics – Flow Cytometric Detection of Urinary Cell Signatures as Noninvasive Approach to Diagnose and Investigate Renal Diseases
Project Description
Simplified, the pillars of the classic laboratory workup of renal diseases consist of an evaluation of the renal glomerular filtration rate (creatinine, cystatin C), assessment of the function of the filtration barrier (proteinuria) and a microscopic analysis of the urine sediment. Analysis of the sediment in particular holds clues to whether an inflammatory kidney disease is present. However, it mainly relies on a semi-quantitative evaluation of unstained cells, is observer-dependent and does not have a high sensitivity or specificity. Normally the urine is almost devoid of immune cells and contains only small numbers of epithelial cells. This changes dramatically in different renal diseases. In previous studies we were able to demonstrate high numbers of urinary CD4+ T cells in patients with active lupus nephritis (LN) using flow cytometry. Applying the amount of urinary T cells as a biomarker in a systemic lupus eythematosus cohort (n=147) we were able to detect patients with acute LN with a very high sensitivity and specificity. Interestingly, monitoring the amount of urinary T cells in the follow up was able to identify patients with remission and those with refractory disease. Aim of our present work is to establish different cellular signatures in the urine applying flow cytometry. Besides different immune cell subsets we will also detect and quantify renal cells like tubular epithelial cells and podocytes. We predict that the analysis of urinary immune cells, tubular epithelial cells and podocytes will enable us to identify different renal diseases and separate the elements of renal inflammation, acute tubular necrosis and glomerular damage.
Dr. med. Johannes Eschrich
Charité – Universitätsmedizin Berlin, Department of Hepatology and Gastroenterology
Email: johannes.eschrich@charite.de
Fields of Research
- Artificial Intelligence
- Gastrointestinal Oncology
- Cancer Pathology
- Digital Medicine
Project Title
Image-Based Prediction of Clinically Actionable Features in Tumor Biopsies of Liver Cancer Using Deep Learning
Project Description
Artificial intelligence already facilitates many aspects of our daily lives. However, there are comparatively few established applications in clinical medicine so far. As a resident in internal medicine and gastroenterology, I am particularly interested in improving the care of patients with cancer of the digestive tract. Our project focuses on cancer of the liver but is also applicable to other tumor entities. The two most common malignant primary liver tumors are so-called hepatocellular and cholangiocellular carcinomas. These entities represent the second most common cause of cancer related death worldwide. Recent advances in molecular medicine have identified innovate systemic treatments that are specific for certain mutations and should therefore be restricted to patients with these molecular features. However, in certain cases available biopsies do not allow molecular analysis, e.g. due to a lack of material, high costs or missing technological infrastructure. Thus, further analytics tools allowing to improve diagnostic sensitivity and specificity are needed in these patients. In our opinion, this unmet medical need can be addressed by using deep learning-based image analysis of standard histopathological tumor samples. Besides the clinically highly relevant differentiation of the mentioned tumor entities, we are working on the predication of relevant molecular biomarkers, like BRAF, Her2neu, V600E, IDH1/2, FGFR2. In addition, we are developing models to predict clinically relevant information such as response to specific therapy options or recurrence-free survival. In parallel, we are performing laboratory experiments to enrich our database of liver cancer patients with complex molecular features. Our project has the potential to improve clinical workflows of liver cancer diagnosis and treatment. Patients could be preselected according to the machine learning biomarker predications and thus the load of molecular assays and radiological imaging could be reduced. Finally, more patients could benefit from personalized molecular treatment and thus outcomes could be improved.
Dr. med. Mathilde Feist
Charité – Universitätsmedizin Berlin, Department of Surgery
Email: mathilde.feist@charite.de
Fields of Research
- Cancer Immunology
Project Title
Cytokine-Armed Onkolytic Vaccinia Virus for Pancreatic Cancer Therapy
Project Description
Immunotherapy is rapidly evolving and fighting cancer by re-activating the patient’s immune system presents a promising therapeutic strategy in addition to standard treatment options as surgery, chemotherapy, and radiotherapy. In contrast to advances in other solid malignancies, the clinical success of checkpoint inhibitors to unlock T-cell immunity has failed in patients with Ductal Pancreatic Adenocarcinoma (PDAC). PDAC is characterized by an extensive fi broinflammatory stroma interfering with an efficient anti-tumor immune response. Lacking effector T cell infiltration; CD4+ regulatory T cells, myeloid-derived suppressor cells, macrophages and mast cells present the majority of the infiltrating immune cells. Based on the results I obtained during my time as a postdoctoral fellow at Prof. David Bartlett´s laboratory, Department of Surgery, University Pittsburgh Medical Center (UPMC), we hypothesize a favorable strategy to overcome immune evasion in pancreatic cancer might be presented by oncolytic virotherapy. Our preliminary data indicate that application of oncolytic vaccinia viruses offers an effective strategy to induce an efficient anti-tumor T cell response independent of baseline T cell infiltration. Furthermore, in combination with checkpoint blockade oncolytic virotherapy elicits systemic and potent anti-tumor immunity. The project aims to explore the therapeutic potential of cytokine-armed oncolytic vaccinia virus for pancreatic cancer in a preclinical model reflecting human disease. The combination of oncolytic virotherapy with a specific stroma effect as well as checkpoint blockade to provide long-term anti-tumor memory may translate into clinical trials in human patients in the near future.
Dr. med. Linda Feldbrügge
Charité – Universitätsmedizin Berlin, Department of Surgery
Email: linda.feldbruegge@charite.de
Fields of Research
- Liver Fibrosis
- Purinergic Signaling
- Macrophage Physiology
Project Title
Purinergic Immune Regulation in Acute and Chronic Liver Injury
Project Description
Liver fibrosis is caused by various chronic liver diseases, including inflammatory, toxic and metabolic diseases, and can result in liver cirrhosis and organ failure. Liver cirrhosis is among the ten most frequent causes of death in Germany. Liver transplantation remains the only therapeutic option of end-stage liver cirrhosis. Further research is needed to better understand the underlying pathophysiology, to refine non-invasive diagnostic tools and develop effective antifibrotic therapies. Liver fibrosis is characterized by excessive formation of scar tissue that replaces healthy liver cells, mainly produced by activated hepatic stellate cells that transdifferentiate into myofibroblasts. Different subsets of macrophages modulate the activation of stellate cells and thereby regulate development and resolution of fibrosis. The functions of both macrophages and stellate cells are controlled by their microenvironment that is altered by inflammatory and metabolic changes in surrounding cells, including the secretion of cytokines and metabolites into the surrounding extracellular space. Purinergic signaling by extracellular purines such as ATP and adenosine is one of the pathways that effect both macrophage phenotype and stellate cell differentiation. ATP is secreted in situations of cell stress, cell death and inflammation. The CD39 family of ectonucleotidases controls the concentrations of extracellular ATP and adenosine by hydrolyzing ATP and ADP to AMP which is further degraded to adenosine. Members of this family are expressed on macrophages and have also been observed on circulating cellular microparticles. The project aims to further define the underlying cellular and molecular mechanisms of purinergic regulation of macrophage function in liver fibrosis.
Dr. med. Lucia Katharina Feldmann
Charité – Universitätsmedizin Berlin, Department of Neurology and Experimental Neurology
Email: lucia.feldmann@charite.de
Fields of Research
- Parkinson's disease
- Deep Brain Stimulation
- Neuromodulation
Project Title
Towards the Clinical Implementation of Adaptive Neurostimulation: Evaluation of Chronic Electrophysiological Biomarkers
Project Description
Deep brain stimulation (DBS) is an established, effective therapy for movement disorders, improving motor symptoms and restoring a better quality of life. Moreover, the possibility to record electrophysiological activity in the basal ganglia through the implanted DBS electrodes has expanded the pathophysiological understanding of movement disorders. Beta frequency band (13-35 Hz) activity in the subthalamic nucleus (STN) is characteristic for Parkinson’s disease (PD) and a potential biomarker, as activity levels correlate with symptom severity and are modulated through therapy. Adaptive DBS (aDBS) is a concept aiming to provide stimulation titrated to the real-time analysis of biomarker activity. To date, most aDBS studies have been limited to short-term experimental, acute peri-operative settings, and little is known about the validity of beta-band activity as a chronic biomarker. Using the novel Percept neurostimulator (Medtronic, Minneapolis, USA), STN local field potential recordings can now be streamed from chronically implanted DBS electrodes, with the advantage of electrophysiological recordings over long time periods, in freely moving patients, and without acute peri-operative limitations. We hypothesize that beta band activity is a stable, chronic electrophysiological biomarker for longterm application in everyday-life, reflecting motor performance, affective symptoms and therapy effects. In the first study part, a cohort of chronically implanted PD patients (>3 months after DBS surgery) will participate in a monopolar review with stepwise stimulation increase and corresponding motor performance assessments, ON and OFF dopaminergic medication. This allows the evaluation of therapy effects and symptom severity in relation to biomarker activity. In a second step, long-term characteristics of biomarker peak activity will be assessed for two weeks, in relation to factors such as motor activity, mood, therapy changes or circadian rhythms documented in patient diaries and clinical scores. Overall, the results of this study will provide a better understanding of chronic biomarker dynamics. As the Percept neurostimulator also has the potential of aDBS therapy, this study lays the foundation for the implementation of neurophysiological research in therapy optimization, towards the clinical application of personalized adaptive neurostimulation.
PD Dr. med. Andreas Fischer
Charité – Universitätsmedizin Berlin, Department of Hepatology and Gastroenterology
Email: andi.fi scher@charite.de
Project Title
Studies on the Functional Role of the Protein Kinase PKN1 in the Regulation of the Intestinal Barrier Function
Project Description
The intestinal barrier represents an essential interface within the human body, separating the intestinal lumen from the finely regulated interior milieu. Numerous in vivo and in vitro observations demonstrate that disruptions of this barrier play a significant role in the pathogenesis
of chronic inflammatory bowel diseases by leading to an uncontrolled transfer of antigens into the
interstitium, which may subsequently lead to the initiation of an inflammatory response. Changes in the structure and function of the tight junctions between neighboring epithelial cells are of particular importance; however, the responsible molecular mechanisms have only been incompletely characterized so far. In particular, the signal transduction pathways that mediate barrier disruption induced by proinflammatory cytokines such as TNFα are not fully known, and thus a therapeutic approach aimed at improving intestinal barrier function for the treatment of inflammatory bowel disease has not yet been successfully developed. This project focuses on the investigation of whether PKN1 is involved in barrier regulation in intestinal cells. A particular focus here will be to characterize the role that PKN1 plays in mediating TNFα induced barrier dysfunction. Specifically, the following goals are pursued: (1) To investigate the effects of PKN1 activation and inactivation on basic Parameters of the epithelial barrier in vitro. (2) To investigate the role of PKN1 in steroid-induced tight junction sealing in the intestinal epithelium. (3) To investigate the role of PKN1 in TNFα-induced barrier disruption.Dr. med. Florian Nima Fleckenstein
Charité – Universitätsmedizin Berlin, Department of Radiology (including Pediatric Radiology)
Email: florian.fleckenstein@charite.de
Fields of Research
- Interventional Oncology
- Quantitative MR Imaging
- Machine Learning
Project Title
Development of Multipurpose Polymer-Microspheres for the Use of Catheter-Based Embolization
Project Description
»... the vascular catheter can be more than a tool for passive means for diagnostic observations: used with imagination, it can become an important surgical instrument.« Dr. Charles T. Dotter
Catheter-based embolizations form a key treatment pillar in the field of interventional radiology. The broad range of clinical indications reaches from active arterial bleedings to state-of-the-art tumor therapies. Generally, an embolic agent is administered into the target vessel via a previously placed catheter, hence occluding the vessel. In this context, the treatment of primary and metastatic liver tumors take a special role. Transarterial Chemoembolization (TACE) is a minimally invasive procedure per- formed to restrict a tumor’s blood supply while simultaneously locally treating the tumor with high doses of chemotherapeutic drugs. To date, the targeted tumor-feeding arteries are embolized permanently making it impossible to use for re-interventions, while also triggering tu- mor-neoangiogenesis. This leads to a therapeutic dilemma. By developing multi-purpose microspheres that (i) can be used for intra-arterial embolization, (ii) can be loaded with chemotherapeutics and (iii) are degradable, hence offering the option of temporary embolization, we aim to solve this problem. In extensive in-vitro tests, we believe to have identified two materials deriving from gelatine and PMMA, that meet the above-mentioned requirements for an ideal embolization material. Within the next two years we will in-vivo test both newly developed embolization materials in several embolization- and tumor-models and hope to add to the development of new and advanced clinical treatment options.Dr. med. Mareike Frick
Charité – Universitätsmedizin Berlin, Medical Department, Division of Hematology, Oncology and Tumor Immunology
Fields of Research
- Hematopoetic Stem Cells
- Clonal Hematopoiesis and Preleukemia
- Myeloproliferative Syndromes
Project Title
Investigation of Functional Consequences of Clonal Hematopoiesis
Project Description
Clonal hematopoiesis ‐ defined by the presence of a somatic hematologic‐cancer‐associated gene mutation – occurs in the peripheral blood of at least 10% of persons older than 60 years of age without any history of hematologic disorders and defines a premalignant state. The presence of this common phenomenon is associated with an increased risk of hematologic cancers and overall mortality, which cannot be explained by hematologic cancers alone. Clonal hematopoiesis is believed to originate in the stem cell compartment, as mutations occur in the hematopoietic stem cells or in progenitor cells. The most frequent mutations of clonal hematopoiesis belong to four functional groups: (1) epigenetic regulators of transcription (e.g. DNMT3A, ASXL1, and TET2), (2) RNA-processing (e.g. SF3B1, SRSF2, U2AF1), (3) signal transduction (e.g. JAK2, K-/N-RAS, STAT3), and (4) tumor suppressors and oncogenes (e.g. TP53, BRCC3). Function- al relevance of these mutations has been demonstrated in mouse models. If the mutation occurs at a variant allele frequency of at least 2%, the phenomenon is called clonal hemaptopoesis of indeterminate potential (CHIP). At present, caution is needed when predicting clinical consequences from a cancer‐associated gene mutation, especially with regard to the stem cell compartment. In the first part of the project, I investigate the effect of CHIP on the differentiation process of hematopoietic stem cells in elderly individuals without cancer using targeted deep sequencing in flow-sorted cell fractions. A second part of my project aims at describing the clinical effects of CHIP in elderly patients with solid cancer receiving myelotoxic (radio-)chemotherapy, looking at outcome parameters such as frequency of neutropenic fever, transfusion necessity, chemotherapy dose reductions, etc. Clonal dynamics under the evolutionary pressure of chemotherapy are also investigated.
Dr. med. Dr. phil. Eva Friedel
Charité – Universitätsmedizin Berlin, Department for Psychiatry and Psychotherapy
Email: eva.friedel@charite.de
Fields of Research
- Learning and Cognition
- Imaging Genetics and Epigenetics
- Alcohol Use Disorder
Project Title
Imaging Genetics and Epigenetics in Alcohol Use Disorder
Project Description
Alcohol dependence and harmful use are partially heritable with an estimated contribution of genetics to phenotypic variance of between 40-60%. Recent large genome wide association studies (GWAS) have identified specific genetic variants, however such association studies require extremely large sample sizes. The combination of genetics and imaging data (referred to as imaging genetics) facilitates the identification of genetic risk variants in considerably smaller sample sizes. The first goal of this project therefore is to identify intermediate phenotypes at the brain level using imaging genetics that can, in a subsequent step, be used for classification or clinical prediction purposes allowing the consideration of genetic as well as epigenetic information. To facilitate this goal, we have collected blood and fMRI data from 150 patients with Alcohol Use Disorder and 200 Healthy Controls and will continue to collect 130 patients with Alcohol Use Disorder for replication. All patients performed basic learning paradigms during fMRI. The specific aims of the project are: To (1) perform chip-based genome wide genetic analyses of all samples and longitudinal epigenetic analyses of selected candidate genes in patient samples; (2) to identify and replicate intermediate brain phenotypes of dysfunction- al learning based on known risk variants (including poly- genetic risk scores and epigenetic information as well as neuroplastic biomarkers such as BDNF) using the standard (voxel based) and a »connectomics« (network based) approach to imaging data; (3) to use the identified intermediate brain phenotypes and epigenetic information for classification and prediction purposes.
Dr. med. Vivien Leonie Friedrich
Charité – Universitätsmedizin Berlin, Department of Neonatology
Email: vivien.friedrich@charite.de
Fields of Research
- Brain Development
- Oligodendroglia and Purkinje Cells
- Hyperoxia
Project Title
Disturbed Interaction of Purkinje Cells and Oligodendroglia in the Postnatal Cerebellum Caused by Oxygen
Project Description
Preterm birth is one of the major pediatric problems worldwide. Although advances in medical care led to increased survival, long-term neurodevelopmental disability remains an area of concern. The impact of preterm birth on psychomotor and behavioral development is reflected in diverse neurological problems such as delayed neurobehavioral development, poor cognition and academic performance. The risk of neurological sequelae after preterm birth rises with prematurity of the neonate. Recent studies of neonatal brain damage focus on the cerebellum. Brain expansion increases in the last trimester of pregnancy. The cerebellum reaches a growth rate that cannot be found in any other brain region. Human birth leads to increased oxygen tension levels in the blood even without supplemental oxygen administration. The relative hyperoxia hits the immature cerebellum of preterm infants in a phase of very dynamic growth and cellular development indicating a high vulnerability to external toxic stimuli. Our goal is to investigate the impact of oxygen toxicity on neonatal brain development in a hyperoxia rodent model. In our previous studies, we could show short- and long-term injuries of the cerebellum caused by hyperoxia. We investigated impaired neu- ronal and impaired oligodendroglial development, which is also seen in preterm infants. The development of oligodendroglia is highly dependent on interactions with neurons. Cerebellar development is regulated by the Purkinje cell neuron. We now aim to investigate in the impact of Purkinje cell injury on oligodendroglial development. We intend to analyze A) the influence of hyperoxia to the function and development of Purkinje cells, B) the interaction of Purkinje cells and oligodendroglia after hyperoxia exposure and c) the influence of GAB- A/-antagonist as a major transmitter released by Purkinje cells on the development of oligodendroglial precursor cells.
Dr. med. Steffen Fuchs, MSc
Charité – Universitätsmedizin Berlin, Department of Pediatrics, Division of Oncology and Hematology
Email: steffen.fuchs@charite.de
Fields of Research
- Neuroblastoma
- Gene Expression Regulation
- Circular RNAs
Project Title
The Role of Circular RNAs in Neuroblastoma
Project Description
Neuroblastoma, an embryonal tumor arising from peripheral sympathetic neuron precursor cells, is the most common extracranial solid tumor of childhood. Approximately half of all children diagnosed with neuroblastoma present with high-risk disease, for which therapeutic options are aggressive and have limited cure rates of at most 40%. No curative therapeutic options currently exist for relapsed neuroblastoma, emphasizing the urgent need for the development of new strategies. Circular RNAs (circRNA) arise by a form of alternative splicing, termed backsplicing, and have recently emerged as a new class of non-coding RNAs important for regulating gene expression. They bind miRNAs or RNA binding proteins via specific sequences to inhibit their function and directly influence transcription. Circular RNAs were recently shown to be highly abundant in neural tissues, especially during development. This makes them particularly interesting for the pathogenesis of neuroblastoma. In this project, we will identify and functionally characterize candidate circRNAs in neuroblastoma. For this purpose, we will establish an RNA Sequencing pipeline to specifically detect circRNAs in neuroblastoma tissue samples covering the whole spectrum of disease. More- over, we will create cell line models that represent the most important genetic alterations in this tumor identity. Identified circRNAs will be validated in vitro in neuroblastoma cell lines and functionally characterized. Ultimately, our aim is to describe functional networks of circRNAs, inhibited miRNAs and downstream oncogenes, tumor suppressors or kinases. In this way, we hope to not only add to the current understanding of neuroblastoma pathogenesis, but also define new druggable targets and associated predictive biomarkers for high-risk disease.
Eva Maria Funk
Charité-Universitätsmedizin Berlin, Institut für Medizinische Genetik und Humangenetik (CVK)
Email: eva-maria.funk@charite.de
Project Title
The relevance of LYVE1 and its expression by the kidney lymphatic vasculature in renal health and disease
Project Description
One in ten people worldwide suffers from chronic kidney disease, in which vital kidney function is gradually lost. To date, there is no effective way to halt the progression to kidney failure and ultimately death. With patient numbers estimated to rise, there is an urgent need for new drug targets.
One promising biological structure are the lymphatics, a vascular network distributed throughout the body, involved in fluid homeostasis and immune surveillance. Recent research has shown that lymphatics are relevant for a multitude of pathologies. However, our understanding of lymphatic vessels in the healthy and diseased kidney is still in infancy. One widely used marker for lymphatic vessels is the protein of interest of this study LYVE1, a hyaluronan receptor involved in immune cell uptake.
A powerful methodological tool for studying vascular systems such as the lymphatics is three-dimensional (3D) microscopy. In comparison to conventional histology, 3D imaging allows an unrestricted evaluation of vessel structures and spatial relationships within large volumetric tissues, without information loss as no physical sectioning is necessary. A current limitation of 3D histology are oftentimes insufficient penetration depths and time-consuming incubation times that occur when using large IgG antibodies for immunofluorescence staining. To overcome this bottleneck, this project involves the generation, production and application of an anti-mLYVE1 single-domain antibody for wholemount immunostaining of entire murine organs. Single-domain antibodies, often referred to as nanobodies, are highly specific 15kDa antibodies which are able to rapidly and satisfactorily penetrate large samples while maintaining favourable antibody features. Using single-domain antibody based wholemount immunostaining, state-of-the-art 3D microscopy techniques and sophisticated quantitative 3D image analysis techniques, the expression levels of LYVE1 in the kidney are compared with those in other organs to investigate a preliminary suggested restriction within the kidney. In addition, the expression of LYVE1 during kidney development at different time points is studied. Finally, potentially altered expression patterns during inflammation in kidney disease and possible effects on immune cell clearance are being explored.
Overall, this project will provide new insights into renal and lymphatic biology that are highly needed to identify novel treatment options for kidney disease.Dr. med. Theresa Gerhardt
Charité – Universitätsmedizin Berlin, Department of Cardiology
Email: teresa.gerhardt@charite.de
Fields of Research
- Vascular immunology in acute coronary syndromes caused by Plaque Erosion
Project Title
Characterization of the Function of T-Adaptive Immunity in Different Pathophysiologies of Acute Coronary Syndrome
Project Description
Rupture of atherosclerotic plaque is the most common cause of acute coronary syndrome (ACS with ruptured fibrous cap, RFC-ACS). In about one third of ACS-events, however, the causative acute pathology is plaque erosion, characterized by coronary thrombus formation at a culprit plaque with intact fibrous cap (IFC-ACS). The pathomechanism of this important pathology is largely unknown. Within the translational OPTICO-ACS study program, we recently observed significant enrichment of cytotoxic- and helper T-cells selectively at the culprit lesion site of IFCACS, but phenotypical and functional details of the observed T-cell response remain unknown. In a delicate balance, the principal CD4+ T-helper (TH)-subsets (regulatory T cells (Tregs, CD127lo,CD25+), TH1- (CXCR3+), TH2- (CCR4+CCR6-), TH17- (CCR4+CCR6+), TH9- (CCR4-CCR6+) and T follicular helper (TFH, CXCR5+) cells) mediate distinct pro-inflammatory, destabilizing (e.g. TH1, TH17) or anti-inflammatory, protective (e.g. Treg, TH2) effects on coronary atherosclerosis. The aim of the current project is in depth characterization of local adaptive immune processes in IFC- and RFC-ACS, using a novel combination of OCT imaging, catheter-based sample acquisition, fl ow-cytometry, multiparameter proteomics and CITE-Seqeuncing.
Dr. med. Lea Gerischer
Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology
Email: lea.gerischer@charite.de
Fields of Research
- Dementia Due to Alzheimers Disease
- Mild Cognitive Impairment
- MRI‐Imaging
Project Title
High resolution MR-Elastography of the Hippocampus in Patients with Alzheimer’s Disease
Project Description
Alzheimer’s disease (AD), the most common cause of dementia, is marked by progressive neurodegenerative changes of brain tissue. One of the regions to be affect- ed early in the course of the disease is the hippocampus. Current diagnostic methods (structural MRI, PET-imaging, and analysis of cerebrospinal fluid) are either invasive or detect changes only late in the course of the dis- ease. The search for non-invasive methods for early diagnosis of the AD is ongoing. MR elastography is a non-invasive technique that measures the elasticity of brain tissue. It has been hypothesized that tissue elasticity is a surrogate parameter for microstructural architecture and therefore an interesting parameter to investigate structural changes of brain tissue in the course of neurodegenerative diseases such as the AD. Whole brain MR elastography has been demonstrated to detect de- creased overall brain stiffness in AD compared to healthy controls. In this project, we investigate whether multi- frequency MR elastography (MMRE) can detect differences in the elasticity of the hippocampus between patients with clinical diagnosis of the AD and healthy controls. This is a pilot study including patients with clinical diagnosis of AD and age- and sex-matched healthy controls. To quantify memory performance, all study participants undergo standardized neuropsychological test batteries (MMSE and CERAD). Further, all study participants undergo a structural MRI-Scan (including T1-, T2- and DTI-sequence) and the MMRE (single-shot EPI-based MRE sequence). The elasticity parameters of the Hippocampus region and a reference region are extracted from the images and compared between the two groups. We hypothesize that patients with AD have lower elasticity measures in the hippocampal region compared to healthy controls. If these hypotheses can be confirmed, the detection of decreased hippocampal stiffness may become a biomarker for early diagnosis and progression monitoring in the AD.
Dr. med. Georg Girke
Dr. med. Carl Christoph Goetzke
Charité – Universitätsmedizin Berlin, Department of Pediatric Neurology
Email: carl-christoph.goetzke@charite.de
Fields of Research
- Autoinflammatory diseases
- Autoinflammation
- Proteasome
- Regulation of inflammation
Project Title
Identification of Novel Genetic Mutations Involved in Proteasome-Assosiated Autoinflammatory Syndrome
Project Description
Monogenic autoinflammatory diseases are characterized by an unprovoked overreaction of the immune system including many organs and are characterized by high morbidity and mortality. An example of a very rare autoinflammatory disease is CANDLE syndrome (»chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature«). This is a proteasome associated autoinflammatory syndrome (PRAAS) in which autoinflammation is triggered by a malfunction in the ubiquitin-proteasome system. The aim of my project is to study an index patient with a so far on a genetic level unexplained cause for his CANDLE syndrome as a basic model to identify further components of the ubiquitin-proteasome system that contribute to autoinflammation. Mutations known so far concern the proteasome-core complex or assembly proteins. We hypothesize that mutations in other proteasome- associated genes may also cause CANDLE syndrome. The aim is to further investigate the causes of CANDLE syndrome. This is expected to yield new insights into the regulation of the ubiquitin-proteasome system, which contributes to inflammation, and additional molecular genetic insights into the regulation of the proteasome or discovery of further proteasome system components, which can be used to develop further therapeutic options for PRAAS/CANDLE syndrome.
Dr. med. Michaela Golic
Charité – Universitätsmedizin Berlin, Department of Obstetrics
Email: michaela.golic@charite.de
Fields of Research
- Fetal Programing After Diabetic Pregnancy
- Uterine Natural Killer Cells in Preeclamptic Pregnancy
Project Title
Epigenetic Modification in Fetuses of Diabetic Pregnancy
Project Description
Intrauterine environment during pregnancy influences offspring later life health, a phenomenon known as fetal programming that has enormous impact on global public health. Maternal physical and mental state, as well as nutrition and life style determine intrauterine environment during pregnancy. Maternal diabetes during pregnancy has an increasing prevalence in western countries of up to 10% of pregnancies. It leads to a pathological intrauterine environment by inducing fetal hyperglycemia and increases risk for diabetes and obesity in offspring later life. The molecular mechanisms for this phenomenon are not well understood, but epigenetic mechanisms influencing gene expression are suspected. We focus on deciphering epigenetic changes and its pathophysiological role in diabetic rat pregnancy. We have shown that rat fetuses of diabetic pregnancy display relevant hypermethylation in the promoter region of Srebf2, a transcription factor and master regulator of cholesterol metabolism, which is paralleled by downregulation of Srebf2 gene expression in liver and brain (Golic et al., Hypertension 2018). We are currently phenotyping adult offspring of diabetic rat pregnancy with regard to glucose and fat metabolism and cardiovascular system to address the pathophysiological relevance of our finding and to elucidate whether the epigenetic changes are persistent. We are also interested in characterizing reversible epigenetic changes and to analyze the environmental factors that induce removal of epigenetic modifications. Knowledge about pathophysiological consequences of epigenetic modifications and its removal could enable development of new therapeutic strategies. In addition, it offers insight into development of diabetes and understanding how environment influences health on a molecular level.
Dr. med. Nina Görlich
Email: nina.goerlich@charite.de
Fields of Research
- kidney transplantation
- transplant immunology
- biomarker
Project Title
Next generation urine diagnostics and monitoring- urine FACS in urinary tract infection
Project Description
Kidney transplantation is proven to provide the best therapeutic option for end stage renal disease. Urinary tract infections (UTI) remain a major challenge in kidney transplant patients due to immunosuppression and deviant anatomy. With an incidence up to 98%, UTI compose a high disease burden to this specific patient group, accompanied by the constantly present risk of transplant deterioration, failure, and higher rejection probability. In previous projects, we were able to establish urine flow cytometry to analyze urine sediments stained by fluorophore-conjugated monoclonal antibodies. Applying urine flow cytometry, we are capable of investigating urinary immune cell populations and kidney cells (proximal tubular epithelial cells, distal tubular epithelial cells, and podocytes) and, thereby, determining urinary cell signatures for specific disorders. The goal of this interdisciplinary project with DRFZ and other partners is (i) to investigate urine cell signature in UTI and (ii) to establish urine bacteria flow cytometry to determine triggering bacterial populations. One key element is to detect urinary immune cell population shifting, indicating occurrence of UTI before patients develop symptoms and before transplant injury develops. With this approach I intend to redefine the diagnostic criteria of UTI, as they are currently defined by appearance of symptoms, and at this time transplant injury is often already present. One of many significant advantages of flow cytometry is the short time frame in which a diagnosis is made. Determination of bacteria populations causing present UTI in a fast manner entails the opportunity to start targeted antibiotic treatment as soon as possible. In comparison, waiting up for microbiological results of urine cultures often takes days in which patients are treated empirically. This project is realized by immune signature and bacteria analysis of urine samples of kidney transplant patients in a longitudinal setting. Patients will separate over the time course into developing UTI (event population) or absence of UTI (control group). With my findings I hope to contribute to enhancing UTI diagnostics, to prevent kidney transplant damage by UTI and to provide a new diagnostic tool to increase kidney transplant survival.
Dr. med. Simon Gräber
Charité – Universitätsmedizin Berlin, Department of Pediatrics, Division of Pneumonology, Immunology
Email: simon.graeber@charite.de
Fields of Research
- CFTR Biomarker
- CFTR Modulator
- Airway Hydration Therapies
Project Title
Functional Characterization, Pharmacological Modulation and Genotype-Phenotype Correlation of Rare CFTR Mutations in Human Airway and Intestinal Epithelia
Project Description
Cystic fibrosis (CF) is the most frequent lethal hereditary disease in Caucasians and is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which results in defective ion transport in epithelial organs. Meanwhile, more than 2000 mutations have been identified in the CFTR gene. Despite the fast development of modulators for common mutations, functional consequences of many rare CF-causing mutations remain unknown. Further, large clinical trials with CFTR modulators in patients with rare CFTR mutations are of- ten impossible. The aims of the project are therefore to first characterize the function of different classes of rare CFTR mutations in human native respiratory and intestinal epithelia, by using sweat test, intestinal current measurement (ICM) and nasal potential difference (NPD), and further correlate the genotype and CFTR function with the clinical phenotype assessed by lung function measurements, anthropometry and lung imaging with MRI. Our final goal is to perform in vitro testing of response to therapy of currently developed and already approved CFTR modulators in patient-derived nasal epithelial cells and intestinal organoids. We believe that studying these questions will provide new insights into the correlation between the CF genotype and CFTR function in the airway and intestinal epithelia and will help to establish mutation-specific therapy for patients with rare CFTR mutations.
Dr. med. Frank Graef
Charité – Universitätsmedizin Berlin, Center for Musculoskeletal Surgery
Email: frank.graef@charite.de
Fields of Research
- Fracture Healing and Traumatic Brain Injury
- Polytrauma
Project Title
Clinical Study on the Phenomenon of Improved Fracture Healing After Traumatic Brain Injury
Project Description
Although the development of modern osteosynthesis techniques within the last 20 years has vastly improved the operative outcome after fracture treatment, we can still observe fracture non-unions in up to 10 %. Non-unions have a tremendously negative effect on the quality of life of patients and generate exuberant health-economic costs. Previous approaches aimed at improving bone healing biologically were only of mediocre success. This is surprising because bone is one of only two organs in humans that can regenerate itself without scar-tissue formation. Patients with long-bone fractures can demonstrate with improved fracture healing and significantly increased callus formation if they suffer from an additional traumatic brain injury (TBI). This is remarkable because increasing degrees of trauma severity can negatively influence bone regeneration. Although the phenomenon of increased callus formation after TBI has long been known to the clinician since the 19th century, the pathological pathways which are triggered after traumatic damage to the brain and accelerate bone healing could not be identified yet. Our research group could already establish a highly standardized and reproducible combined trauma model for mice in which we could reproduce this phenomenon. Furthermore, we could demonstrate that the osteoinductive effect after TBI is dependent on intact leptin signaling. On the basis of the results from our screening studies on mice we hypothesize that changes in energy homeostasis and immunological cellular (CD4/CD8) and humoral (IL-1, IL-6, TNFα) responses after TBI are responsible for the improved fracture healing. In our clinical study, we include patients who are admitted to the emergency room of our trauma department and demonstrate with an isolated long-bone shaft fracture, an isolated TBI or the combination of both injuries. Blood samples and X-rays are taken from the patients in a specific timely manner in order to confirm the results from our studies on mice.
PD Dr. med. Jan Adriaan Graw
Charité – Universitätsmedizin Berlin, Department of Anesthesiology and Operative Intensive Care Medicine
Email: jan‐adriaan.graw@charite.de
Fields of Research
- Acute Respiratory Distress Syndrome
- Hemolysis
- Blood Transfusion
Project Title
Transfusion-Associated Effects of Extra-Cellular Hemoglobin on the Development and Severity of Ventilator-Induced Lung Injury
Project Description
Mechanical ventilation is used to support millions of critically ill patients each year. However, despite its life-saving potential mechanical ventilation can cause injury and complications. The most important adverse effect of mechanical ventilation is the ventilator-induced lung injury (VILI). Among others, patients on the Intensive Care Unit are challenged with increased levels of circulating intravascular cell-free hemoglobin which causes vasoconstriction by depletion of endothelial nitric oxide, oxidative stress, and inflammation. Furthermore, cell-free hemoglobin contributes to tissue injuries such as renal failure and intestinal mucosa damage after cardiac surgery and is associated with an increased mortality in patients with sepsis. Recently, we demonstrated that in- creased plasma concentrations of cell-free hemoglobin and heme after transfusion of stored packed red blood cells potentiate a primary injury induced by prolonged hypotension. With this project, we would like to extend our knowledge and explore in more detail the mechanisms by which cell-free hemoglobin and heme might aggravate VILI. We study whether increased plasma concentrations of cell-free hemoglobin accelerate the development and increase the severity of VILI. Both, VILI and extracellular hemoglobin independently induce sys- temic pro-oxidant and pro-inflammatory effects. There- fore, we explore pulmonary and additional extra-pulmonary foci of inflammation and apoptosis in VILI with and without exposure to cell-free hemoglobin. Furthermore, we study whether the adverse effects caused by cell-free hemoglobin might be attenuated by therapy with the hemoglobin scavenger haptoglobin.
Dr. med. Julius Grunow
Charité – Universitätsmedizin Berlin, Department of Anesthesiology and Operative Intensive Care medicine
Email: julius.grunow@charite.de
Fields of Research
- Intensive Care Unit acquired Weakness
- Translational Research
- Muscle Homeostasis
Project Title
The Impact of Bioenergetic Failure on Muscular Function in Critically Ill Patients
Project Description
Intensive Care Unit-acquired Weakness (ICUAW) is a clinical diagnosis defined by a reduction in maximal muscle strength, which cannot be explained by anything other than critical illness itself. It can be observed in the majority of critically ill patients and is further characterized by an early onset, rapid muscle atrophy. Short-term as well as long-term mortality and morbidity are significantly increased in patients with ICUAW. In a previous project, we discovered that preservation of muscle mass in critically ill patients is not able to counteract development of weakness and further does not improve recovery within one year after ICU discharge. We further noticed that, while muscle strength fully recovered after ICU discharge, muscle endurance remained impaired. During commencement of our trial we performed neuromuscular electrical stimulation and noticed that patients contractile response was highly variable, declined over time and dependent on the degree of illness. An observation that had been disregarded earlier but also cannot be explained by muscle atrophy. These findings led us to the conclusion that limited muscle
endurance, dissociation of muscle mass and muscle strength as well as variable contractile response to neuromuscular electrical stimulation are most likely caused by a dysfunctional energy supply. Considering mitochondria are the main energy provider for the human body and especially for muscle activity extending beyond short bursts of maximal strength, we hypothesized that impaired mitochondrial function – bioenergetic failure – could be the main culprit leading to the observed phenotype. We therefore aim in a first step to do a thorough characterization of mitochondrial function, mitochondrial biogenesis as well as related pathways and in a
second step correlate our molecular findings to the clinical, metabolic and electrophysiological data in order to identify key mechanisms as possible therapeutic targets.Dr. med. Stefan Habringer, Dr. med. univ.
Charité – Universitätsmedizin Berlin, Department of Hematology, Oncology and Cancer Immunology
Email: stefan.habringer@charite.de
Fields of Research
- Translational hematology and oncology
- B-cell lymphoma
- Genetic screening
- Targeted therapies
Project Title
Forward Genetic Screening for Analysis and Therapeutic Targeting of BCL6-Associated Lymphoma
Project Description
BCL6 is a BTB/POZ zinc finger transcription factor acting as a transcriptional repressor in a sequence-specific manner. Without intact BCL6, the GC reaction cannot occur, resulting in failure to produce memory B cells and antibody-producing plasma cells. BCL6 represses various tumor suppressor genes, but also oncogenes to counterbalance the risk of transformation. BCL6 translocations and overexpression occur in up to 50% of DLBCL patients and are present in a subset of patients with adverse prognosis. The IμBCL6 mouse is a lymphoma model carrying a translocation similar to the one found in DLBCL patients, resulting in spontaneous lymphoma development. Strategies to target BCL6 are currently being tested, but drug development for targeting transcription factors and identifying patients who will profit from novel drugs is challenging, especially in high-risk or treatment-resistant patients. In DLBCL, sequencing samples from large, well-annotated patient cohorts have provided us with a plethora of evidence about genetic and non-genetic alterations in this disease. The central challenge is to identify and understand highly relevant functional alterations and distinguish them from less relevant genetic and non-genetic events. The piggyBac (PB) transposon mutagenesis system enables us to screen for functionally relevant cancer genes by activating and inactivating all genes across the whole genome. Thereby, it serves as a complementary approach to the aforementioned patient datasets to answer open questions about novel cancer genes in vivo. In this system, short DNA elements carrying promoters and gene traps called transposons (ATP2 mouse) are randomly integrated into the genome by a transposase (RosaPb mouse), allowing the identification of oncogenes and tumor suppressor genes in a single unbiased experimental approach. Transposon insertion sites can be identified with quantitative insertion site sequencing (QiSeq) with very high resolution as described. We are using PB in the DLBCL-prone IμBCL6 mouse model to fi nd novel candidate genes relevant for lymphomagenesis. Thereby, we aim at identifying clinically relevant mechanisms of lymphoma development and progression, biomarkers for treatment response and resistance, focusing on how to overcome treatment resistance by molecularly targeted therapies.
Dr. rer. nat. Rene Hägerling
Charité – Universitätsmedizin Berlin, Department of Cardiology
Email: rene.haegerling@charite.de
Fields of Research
- Lymphovascular Medicine
- Genetics
- Imaging
- Histopathology
Project Title
Lightsheet Microscopy-Based 3D-Histology of Human Tissue Samples
Project Description
Over the last years, there was a lot of progress in identifying genes, which cause primary lymphedema in humans, but how genetic abnormalities cause lymphedema at the cellular level is still unknown. This lack of mechanistic insight is associated with the absence of suitable microscopic imaging techniques for the visualization of the vasculature as classical 2-dimensional histology is not sufficient to understand the complex lymphatic vessel architecture. This has been one of the major contributing factors to the lack of detailed knowledge of the pathogenesis of lymphedema. To understand the underlying vascular alteration causing lymphedema in more detail and to overcome the limitations of classical histology, we have developed innovative and optimized
immunofluorescence staining protocols for entire tissue biopsies from patients suffering from lymphedema. Following immunofluorescence staining, we apply VIPAR (volume information-based histopathological analysis by 3D-reconstruction and data extraction), a novel diagnostic tool for vascular diseases, on tissue biopsies from lymphedema patients. ViPAR, a lightsheet microscopy- based approach for optical of entire tissue biopsies, is based on digital 3-dimensional reconstruction and allows the visualization of the entire vascular network. Using automated data extraction and analysis algorithms, the underlying histology is described and quantified in 3-dimensional space. This knowledge on the underlying pathology and alterations associated with the disease is a prerequisite for future pharmacological interventions as it supports clinicians’ decision-making by improved patient stratification. In summary, this approach for 3D-histology allows 3-dimensional visualization of the entire blood and lymphatic vasculature in lymphedema patients and therefore facilitate a deep-phenotyping of patients’ tissue, which is not possible by using classical methods, e.g. 2D-histology. By using state-of-the-art imaging techniques, this study will expand our current knowledge on primary lymphedema significantly and will set the basis for new treatment regimens.Dr. med. Adriane Halik
Charité – Universitätsmedizin Berlin, Medical Department, Division of Hematology, Oncology and Tumor Immunology
Email: adriane.halik@charite.de
Fields of Research
- Leukemogenesis
- Acute Myeloid Leukemia
- Single‐Cell Analysis
Project Title
From Clonal Hematopoiesis to Relapsing Leukemia: Tracing the Roots of AML on Single Cell Level
Project Description
Acute Myeloid Leukemia (AML) – the most common type of acute leukemia in adults – remains a demanding challenge for researchers and physicians all over the world with a 5-year survival rate of less than 30%. It originates from early pre-leukemic hematopoietic stem cells which gain additional leukemia-defining mutations over time. In some patients, these pre-leukemic lesions persist in remission after intensive chemotherapy. Reent studies have shown that the persistence of pre-leukemic lesions in these patients associates with a higher risk of disease relapse. Managing disease recurrence embodies a major therapeutic challenge as relapsed AML is accompanied by the high prevalence of therapy resistance. From a molecular point of view, this can be explained by a significant genetic evolution of the tumor genome. In the past few years, multiple next-generation sequencing (NGS) studies have already paved the way for the revelation of the genetic heterogeneity of AML. However, by using bulk DNA, the obtained findings by NGS methods display only an average molecular image of a diverse cell population. In contrast, single-cell DNA genotyping now allows for the revelation of the clonal evolution of the tumor genome and a more precise detection of intercellular variety. Using a combination of whole-exome sequencing (WES) and single-cell DNA genotyping, I aim to unravel the phylogeny of AML and trace the clonal evolution from diagnosis to relapse. Therefore, I will analyze bone marrow and peripheral blood samples from a target cohort of 30 AML patients. WES will be applied to identify tumor-specific genetic target alterations. For Fluidigm-based targeted single-cell genotyping defined flow-sorted stem cell fractions will be used. By means of bioinformatic and statistical analysis, an individual phylogenetic tree will be created for each patient. Hereby, I aim to identify novel therapeutic targets and thus improve the therapeutic management of AML.
PD Dr. med. Leo Hansmann
Charité – Universitätsmedizin Berlin, Medical Department, Division of Hematology, Oncology and Tumor Immunology
Email: leo.hansmann@charite.de
Fields of Research
- Tumor Immunology
- Lymphocyte Differentiation and Function
- Single Cell Technologies
Project Title
Phenotypes, Clonal Relatedness and Functions of Multiple Myeloma-Infiltrating T-Cells
Project Description
Multiple myeloma is characterized by the accumulation of neoplastic plasma cells in the bone marrow and develops from a non-malignant pre-cancer, called monoclonal gammopathy of undetermined significance (MGUS). T-cells influence disease development, therapeutic responses, and survival, yet, little is known about their clonal restriction, differentiation states, and functions at the single cell level. Technologies such as cytometry by time-of-flight (CyTOF) and next generation sequencing allow the high-dimensional detection of even rare immune phenotypes on the single cell and molecular level. We hypothesize bone marrow-infiltrating multiple myeloma-reactive T-cells to show unique immune phenotypes, clonal expansion, and functional aberrations that successively render them incapable of eliminating the malignant T-cells during disease progression. 40-dimensional CyTOF phenotyping and functional analyses of multiple myeloma, MGUS, and healthy bone marrow
will detect unique disease-associated T-cell phenotypes and patterns of disease progression. Parallel single cell sequencing of paired α and β T-cell receptor, cytokine, and transcription factor genes from bone marrow-infiltrating T-cells will identify expanded and most likely multiple myeloma-reactive T-cell clones. The T-cell receptors of predominant clones will be reconstructed, recombinantly expressed, and screened against peptide-MHC libraries to identify their possible ligands. Finally, we will use phosphorylation-specific flow cytometry to determine whether bone marrow lymphocyte signaling alterations are cytokine milieu-driven or T-cell intrinsic. Determining detailed bone marrow lymphocyte phenotypes, clonal relatedness, specificities, and functions, our study will add substantially to the field of multiple myeloma biology and possibly lead to new therapeutic strategies in cancer immunology.Dr. med. Lisa Hartmann
Charité – Universitätsmedizin Berlin, Department of General, Visceral and Vascular Surgery
Email: lisa.hartmann@charite.de
Fields of Research
- Postoperative Ileus
- Small Bowel Obstruction
Project Title
Effect of Preoperative Selective Decontamination of the Digestive Tract (SDD) and Mechanical Bowel Preparation (MBP) on Postoperative Ileus in Mice
Project Description
The phenomenon of postoperative ileus (POI) frequently occurs after abdominal surgical interventions. Consequences of POI are delayed ingestion, prolonged enteral nutrition, pain and sustained hospitalization. In single cases, POI-associated vomiting, followed by aspiration can lead to life-threatening situations. Consequently, the incidence of POI is highly expensive, due to prolonged treatment and patient’s inability to work. Although several aspects of POI pathophysiology are described, intervention procedures or therapies are not effective enough to prevent or inhibit POI completely, so far. Especially, in case of an advanced state, therapeutically intervention is difficult. Therefore, an early intervention during the initial phase seems more promising. In the 1970 ́s the combination of mechanical bowel preparation (MBP) and selective decontamination of the digestive tract (SDD) has been routine practice in colorectal surgery. After research indicating that MBP may be harmful, it has been completely abandoned. Since this decade the discussion came to a renaissance. In 2015 a large retrospective study showed that the combination of MBP with SDD reduces POI in patients. Up to this point, there is a lack of experimental data concerning this matter, especially regarding POI. We induce postoperative ileus in mice after laparotomy and systemic manipulation of the intestine. Afterward, the intestinal barrier dysfunction is being tested in Ussing-chambers and by immunohisto- chemistry. Therefore the aim of our work is to determine whether intestinal permeability and leukocyte infiltration of the intestinal wall decrease during SDD and/or MBP in POI in mice.
Univ.-Prof. Dr. med. Dr. rer. nat. Ahmed Nabil Hegazy
Charité – Universitätsmedizin Berlin, Medical Department, Division of Gastroenterology, Infectiology and Rheumatology
Email: ahmed.hegazy@charite.de
Fields of Research
- Immunological Memory
- Host‐Microbiota Interactions
- Inflammatory Bowel Disease
Project Title
Deciphering Host-Microbiota Interactions in Inflammatory Bowel Disease
Project Description
The mammalian gastrointestinal tract is the largest organ of the human body beside the skin. It is the organ containing the largest number of immune cells and harbours a large and diverse population of commensal bacteria that exist in a symbiotic relationship with the host. In recent years, it has become increasingly clear that the composition of this gastrointestinal microbiome and its interaction with the host immune system strongly influences the health of the host. One disease complex, in which maladaptation in this host microbial dialogue is involved, is inflammatory bowel disease (IBD). Here, this maladaptation leads to an aberrant immune response in the gut, resulting in recruitment of various lymphoid and myeloid effector cell populations and inflammation of gut tissue. The exact aetiology of IBD remains uncertain, but it is a multifactorial disease that involves a complex interplay between genetic, environmental, microbial, and immune factors. Deciphering the complex interplay between both the genetic and environmental factors and the microbiota, is therefore of great biomedical importance. By combining mouse and human T cell immunology, mucosal immunology and animal models of disease as well as clinical specimens, we aim to identify environmental, microbial, and inflammatory drivers that promote maladaptation and gut tissue inflammation. We use a combination of cutting edge technologies, high through- put culture methods, cell and organoid cultures, physiological mouse models of colitis and analysis of well defined patient cohorts. We specifically aim to uncover new pathways involved in induction and regulation of tissue resident T cells, bacterial interaction and intestinal inflammation that may offer new therapeutic targets in inflammatory diseases such as IBD.
Dr. med. Maria Heinrich
PD Dr. med. Julian Hellmann-Regen
Charité – Universitätsmedizin Berlin, Department of Psychiatry
Email: julian.hellmann@charite.de
Fields of Research
- Retinoic Acid Homeostasis in Psychiatric Disorders
- Neuroinflammation in Psychiatric Disorders
Project Title
Retinoic Acid Homeostasis in Major Depression
Project Description
The central research question of this project is to elucidate a putative link between an altered retinoic acid (RA) signaling in the pathogenesis of major depression. RA, the most active metabolite of Vitamin A, plays a key role as a morphogen during embryonic development and represents an endogenous neuroprotectant and anti-inflammatory agent in the adult CNS. Several lines of evidence suggest altered cerebral RA signaling in affective disorders. Preliminary own work has demonstrated strong effects on local RA-homeostasis for select antidepressants and also for the pleiotropic anti-inflammatory antibiotic minocycline, for which antidepressant effects have recently been discussed on the basis of its potent actions on microglial cells, inhibiting microglial activation. Therefore, we will further investigate putative RA-modulating effects of minocycline and of several antidepressants in a preclinical subproject. In parallel, we will assess altered parameters of RA-homeostasis in drug-free depressed patients and matched controls. Furthermore, we will conduct a randomized, placebo-controlled clinical trial to assess putative anti-depressant effects of minocycline in so far treatment-refractory depressed patients. In the same study, we will systematically assess an impact of minocycline on RA-homeostasis-related parameters over a 6-week time course of treatment with minocycline or placebo. Elucidating a role for RA-Homeostasis in the pathogenesis and treatment of major depression will be an important step in the development of more targeted interventions to treat depressed patients, particularly those not responding to standard treatments.
Prof. Dr. med. Anton G. Henssen
Charité – Universitätsmedizin Berlin, Department of Pediatrics, Division of Oncology and Hematology
Email: anton.henssen@charite.de
Fields of Research
- Pediatric Cancer Genomics
- Personalized Cancer Therapies
- Pediatric Solid Tumor Biology
Project Title
Understanding the Origin of Complex Structural Variants in Pediatric Cancer Genomes
Project Description
Significant tumor regression can be achieved in many cancers by induction chemotherapy. The period of remis- sion varies, and is too often followed by regrowth of aggressive, therapy-resistant lesions. Treatment resistance is believed to be partly driven by the pre-existence of resistant phenotypes within the clonal population of the cancer in a single patient. Neuroblastoma is a prototypical example of this phenomenon. Neuroblastomas are the most common tumor in childhood. The majority of high-risk neuroblastomas are sensitive to induction therapy, but quickly recur as chemotherapy-resistant disease that is almost uniformly lethal. Neuroblastoma is characterized by a surprising paucity of gene mutations. However, recurrent chromosomal and complex genomic rearrangements, including chromothrypsis and double minutes, are common in high-risk neuroblastomas. It remains largely unknown what drives neuroblastoma intratumoral heterogeneity, chemotherapy resistance and disease relapse.We have made new discoveries linking DNA recombinases to sequence-specific oncogenic mutations (as published in Nature Genetics and Science Translational Medicine in 2017), which has direct implications for the understanding of genomic structural variation in pediatric tumors. We aim to determine the molecular mechanisms of recombinase-induced genomic plasticity and adaptation to targeted therapies using functional investigation of human tumors and engineered animal mod- els, with the long-term goal of developing rational combination therapy for patients with high-risk, refractory or relapsed pediatric solid tumors. The development and use of functional genomics tools will feature strongly in our group, and work in our lab will focus on investigating the dysregulated organization of cancer cell genomes with the goal of identifying effective targets and therapeutic agents for rationally designed combination therapies.
Dr. med. Anton G. Henssen
Charité – Universitätsmedizin Berlin, Department of Pediatrics, Division of Oncology and Hematology
Email: anton.henssen@charite.de
Fields of Research
- Pediatric Cancer Genomics
- Personalized Cancer Therapies
- Pediatric Solid Tumor Biology
Project Title
Understanding the Origin of Complex Structural Variants in Pediatric Cancer Genomes
Project Description
Significant tumor regression can be achieved in many cancers by induction chemotherapy. The period of remis- sion varies, and is too often followed by regrowth of aggressive, therapy-resistant lesions. Treatment resistance is believed to be partly driven by the pre-existence of resistant phenotypes within the clonal population of the cancer in a single patient. Neuroblastoma is a prototypical example of this phenomenon. Neuroblastomas are the most common tumor in childhood. The majority of high-risk neuroblastomas are sensitive to induction therapy, but quickly recur as chemotherapy-resistant disease that is almost uniformly lethal. Neuroblastoma is characterized by a surprising paucity of gene mutations. However, recurrent chromosomal and complex genomic rearrangements, including chromothrypsis and double minutes, are common in high-risk neuroblastomas. It remains largely unknown what drives neuroblastoma intratumoral heterogeneity, chemotherapy resistance and disease relapse.We have made new discoveries linking DNA recombinases to sequence-specific oncogenic mutations (as published in Nature Genetics and Science Translational Medicine in 2017), which has direct implications for the understanding of genomic structural variation in pediatric tumors. We aim to determine the molecular mechanisms of recombinase-induced genomic plasticity and adaptation to targeted therapies using functional investigation of human tumors and engineered animal mod- els, with the long-term goal of developing rational combination therapy for patients with high-risk, refractory or relapsed pediatric solid tumors. The development and use of functional genomics tools will feature strongly in our group, and work in our lab will focus on investigating the dysregulated organization of cancer cell genomes with the goal of identifying effective targets and therapeutic agents for rationally designed combination therapies.
PD Dr. med. Bernd Hewing
Charité – Universitätsmedizin Berlin, Medical Department, Division of Cardiology and Angiology
Email: hewing@kardiologie-muenster.de
Fields of Research
- Atherosclerosis
- Inflammation
- Interventional Cardiology
Project Title
iRhom2 in Atherosclerosis
Project Description
Tumor necrosis factor (TNF)-alpha is a potent inflammatory mediator that plays an important role in the development of atherosclerosis. It is expressed as a precursor transmembrane protein and subsequently converted into its soluble, bioactive form by TNF-alpha converting enzyme (TACE) mediated shedding. Recently discovered inactive rhomboid protein 2 (iRhom2) is essential for maturation of TACE in immune cells. A genetic knock-out or knock-down of iRhom2 results in a loss of TACE activity and, consequently, in a markedly reduced shedding of TNF-alpha in cells involved in atherosclerosis such as macrophages. iRhom2-deficient mice exhibit reduced serum levels of TNF-alpha in response to inflammatory stimuli, survive otherwise lethal doses of LPS and are protected from the development of inflammatory arthritis. These findings strongly suggest that the iRhom2/TACE/TNF-alpha signaling axis may contribute to atherosclerosis. However, to date, this hypothesis has not been tested experimentally. Therefore, our group evaluates the impact of iRhom2 on atherosclerotic plaque development and on phenotypic and functional characteristics of macrophages as well as the pathophysiological role of iRhom2 in patients with coronary artery disease. Taken together, this project aims at characterizing the role of iRhom2 in atherosclerosis and thus contributes to better understanding of inflammatory processes in atherosclerosis and the development of novel therapeutic strategies for the treatment of this disease.
Dr. med. Karl Herbert Hillebrandt
Charité - Universitätsmedizin Berlin, Department of Surgery
Email: karl-herbert.hillebrandt@charite.de
Fields of Research
- Regenerative Medicine/Oncology
Project Title
Decellularized Human Liver Slices as a Three-Dimensional Platform to Generate In Vitro Intrahepatic Cholangiocarcinoma
Project Description
Intrahepatic cholangiocarcinoma (iCCA) is the second most common tumor entity of the liver. The only curative treatment options for patients suffering from an iCCA is surgical resection. iCCA show a high rate of intrahepatic recurrence, which was found to be up to 60 %. For patients with recurrence, primary metastatic cancer, lymph node metastasis or R1 resection, chemotherapy or local ablative therapies are the remaining treatment options. Unfortunately, these therapeutic concepts have poor response rates. Considering this there is the need to explore new therapeutic options: In vitro models are essential tools to investigate tumor biology and the effect of certain pharmaceuticals. Despite iCCA cell lines and 2D primary cell cultures gave insights into the biology of these tumors, they have some important drawbacks like the poor translational value due to the artificial culture conditions. New approaches for in vitro studies are the formation of 3D spheroids and organoids. Nevertheless, these approaches have also shown a selection of tumor cells and tumor-organoids still showed differences in mutations-patterns in comparison to native tumor tissue. In a recently published study, the value of decellularized rat lung and liver tissue on the in vitro formation of colorectal metastasis has been described. We hypothesize that decellularized human liver tissue will promote the in vitro tumor formation of iCCA tumors with a better preservation of tumor microenvironment, genetic mutation pattern and therefore will reflect a better clinical correlation for adjuvant treatments in comparison to 2D primary culture and tumor organoids.
Dr. med. Dipl.-Math. Christian Hinze
Charité – Universitätsmedizin Berlin, Medical Department, Division of Nephrology
Email: christian.hinze@charite.de
Fields of Research
- Acute Kidney Injury
- Single Cell Sequencing
- Polycystic Kidney Disease
Project Title
Transcriptional Regulation in Healthy and Diseased Kidney Tissue
Project Description
Kidneys of higher mammals comprise a complex ensemble of many different T-cell types including renal tubules, immune and interstitial cells, to mention but a few. Renal tubules are again subdivided into distinct tubular segments serving the excretion of toxins and participating in body water and electrolyte homeostasis. The renal collecting ducts constitute the most distal part of the renal tubules and are responsible for urine finetuning including electrolyte and water reabsorption. We were recently able to uncover the role of a collecting duct-expressed transcription factor, grainy- head-like 2 (GRHL2), which mediates collecting duct tightness and barrier function (Aue, Hinze et al., JASN, 2015; Hinze et al., JASN, 2018). Lack of collecting duct GRHL2 led to a constant loss of electrolytes and free water and a susceptibility to prerenal acute kidney injury. We could show that GRHL2 orchestrates a set of genes involved in cell-cell junction formation and maintenance in renal collecting ducts. However, the vast heterogeneity of cells forming the kidney drastically complicates the analysis of physiological and pathological renal processes. Each cell type has a distinct role in health and can become an outcome-determining population in disease. Cell type behavior and functions are mainly determined by distinct transcriptional gene expression programs. So far, researchers used a combination of microdissection followed by RNA sequencing to uncover renal transcriptional programs in various settings. We were recently able to establish single-cell RNA sequencing in our lab. This technology facilitates the investigation of gene expression in individual cells and cell populations. With it, we want to deepen our understanding of GRHL2 function in the kidney but also apply it to clinical questions such as in polycystic kidney disease.
Dr. med. Christian Johannes Hoffmann
Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology
Email: christian.hoffmann@charite.de
Fields of Research
- Molecular Stroke Research
- Neuroregeneration After Stroke
- Inflammation After Stroke
Project Title
Influence of Endothelial IL6/Stat3 Signaling on Angiogenesis, ECM Remodeling and Neuro-Plasticity After Stroke
Project Description
Stroke is the second leading cause of death and the leading cause of disability worldwide. Treatment is limited to a narrow time window of 4.5 h, but fewer than 10% of patients benefit from this, and many are left with severe, lasting disabilities. A treatment focused on improving regeneration and functional recovery in the long term would be of great benefit, indeed, the brain harbors endogenous mechanisms to improve neuronal network rewiring. Interleukin 6 (IL6) is associated with higher risk for atherosclerosis and stroke and increased blood IL6 levels correlate with worse outcome. However, other studies have reported IL6 in the acute phase of stroke is able to reduce lesion size. The pleiotropic effects of IL6 might be explained by complex signaling mechanisms that differ according to the cell type involved and the condition of the tissue microenvironment. We have shown that downstream IL6 signaling of endothelial Signal transducer and activator of transcription 3 (Stat3) is of high importance for remodeling of the extracellular matrix (ECM), promotion of angiogenesis and functional recovery. We hypothesize that paracrine IL6 signaling within the neurovascular niche can improve neuronal network rewiring and functional recovery. We generated a mouse model for cell-specific and inducible expression of IL6 (FLEX-IL6). The secreted IL6 is subsequently detectable by a fused myctag. IL6 secretion will be induced 2 days after stroke to focus on regenerative mechanisms, rather than preventing acute cell death. We will analyze the effects on functional recovery, angiogenesis, and ECM remodeling. IL6 acts on the CST (tracible by the fused myc-tag), when it is secreted by astrocytes. We will further explore this relationship by using laser capture microdissection to excise IL6 positive CST bundles in order to characterize protein expression. Effects on network rewiring and CST regeneration will be visualized by tract-tracing methods, MRI connectivity analysis, and pharmacogenetic inhibition methods (DREADD).
Dr. med. Christian Johannes Hoffmann
Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology
Email: christian.hoffmann@charite.de
Fields of Research
- Molecular Stroke Research
- Neuroregeneration After Stroke
- Inflammation After Stroke
Project Title
Influence of Endothelial IL6/Stat3 Signaling on Angiogenesis, ECM Remodeling and Neuro-Plasticity After Stroke
Project Description
Stroke is the second leading cause of death and the leading cause of disability worldwide. Treatment is limited to a narrow time window of 4.5 h, but fewer than 10% of patients benefit from this, and many are left with severe, lasting disabilities. A treatment focused on improving regeneration and functional recovery in the long term would be of great benefit, indeed, the brain harbors endogenous mechanisms to improve neuronal network rewiring. Interleukin 6 (IL6) is associated with higher risk for atherosclerosis and stroke and increased blood IL6 levels correlate with worse outcome. However, other studies have reported IL6 in the acute phase of stroke is able to reduce lesion size. The pleiotropic effects of IL6 might be explained by complex signaling mechanisms that differ according to the cell type involved and the condition of the tissue microenvironment. We have shown that downstream IL6 signaling of endothelial Signal transducer and activator of transcription 3 (Stat3) is of high importance for remodeling of the extracellular matrix (ECM), promotion of angiogenesis and functional recovery. We hypothesize that paracrine IL6 signaling within the neurovascular niche can improve neuronal network rewiring and functional recovery. We generated a mouse model for cell-specific and inducible expression of IL6 (FLEX-IL6). The secreted IL6 is subsequently detectable by a fused myctag. IL6 secretion will be induced 2 days after stroke to focus on regenerative mechanisms, rather than preventing acute cell death. We will analyze the effects on functional recovery, angiogenesis, and ECM remodeling. IL6 acts on the CST (tracible by the fused myc-tag), when it is secreted by astrocytes. We will further explore this relationship by using laser capture microdissection to excise IL6 positive CST bundles in order to characterize protein expression. Effects on network rewiring and CST regeneration will be visualized by tract-tracing methods, MRI connectivity analysis, and pharmacogenetic inhibition methods (DREADD).
Dr. med. univ. Felix Hohendanner, PhD
Charité – Universitätsmedizin Berlin, Department of Cardiology
Email: felix.hohendanner@charite.de
Fields of Research
- Experimental Cardiology
Project Title
Electrical and Mechanical Dysfunction in Atrial Cells During Diastolic Heart Failure
Project Description
Atrial remodeling (enlargement, contractile dysfunction) and atrial arrhythmias are often observed in heart failure and are associated with worse clinical outcomes. In heart failure with preserved ejection fraction (HFpEF) atrial remodeling is particularly common for further compromising left ventricular filling. A variety of mechanisms including increased left ventricular diastolic pressure and neurohumoral activation have been linked to atrial remodeling in HFpEF. However, the cellular mechanisms leading to atrial dysfunction in HFpEF remain elusive. We use echocardiography, MRI, in-vivo hemodynamics and state of the art cellular imaging techniques (e.g. FRET imaging, local photoactivation, ratiometric and non-ratiometric confocal Ca2+/Na+ live cell imaging) to study atrial remodeling in HFpEF. Aims of the current project are: 1) to characterize mechanisms that
lead to contractile and/or rhythm dysfunction during atrial remodeling in a rat HFpEF-model, caused by metabolic syndrome, as well as in human myocardium with an emphasis on Inositol-1,4,5-triphosphate (IP3)-receptor mediated Ca2+ release, and the activity of the Na+/ Ca2+ exchanger (NCX); 2) to identify pharmacological targets for the treatment of atrial dysfunction in HFpEF.PD Dr. med. univ. Felix Hohendanner, PhD
Charité – Universitätsmedizin Berlin, Department of Cardiology
Email: felix.hohendanner@charite.de
Fields of Research
- Experimental Cardiology
Project Title
Electrical and Mechanical Dysfunction in Atrial Cells During Diastolic Heart Failure
Project Description
Atrial remodeling (enlargement, contractile dysfunction) and atrial arrhythmias are often observed in heart failure and are associated with worse clinical outcomes. In heart failure with preserved ejection fraction (HFpEF) atrial remodeling is particularly common for further compromising left ventricular filling. A variety of mechanisms including increased left ventricular diastolic pressure and neurohumoral activation have been linked to atrial remodeling in HFpEF. However, the cellular mechanisms leading to atrial dysfunction in HFpEF remain elusive. We use echocardiography, MRI, in-vivo hemodynamics and state of the art cellular imaging techniques (e.g. FRET imaging, local photoactivation, ratiometric and non-ratiometric confocal Ca2+/Na+ live cell imaging) to study atrial remodeling in HFpEF. Aims of the current project are: 1) to characterize mechanisms that
lead to contractile and/or rhythm dysfunction during atrial remodeling in a rat HFpEF-model, caused by metabolic syndrome, as well as in human myocardium with an emphasis on Inositol-1,4,5-triphosphate (IP3)-receptor mediated Ca2+ release, and the activity of the Na+/ Ca2+ exchanger (NCX); 2) to identify pharmacological targets for the treatment of atrial dysfunction in HFpEF.Dr. med. Judith Holstein
Dr. med. Andreas Horn, MD, PhD
Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology
Email: andreas.horn@charite.de
Fields of Research
- Deep Brain Stimulation
- Movement Disorders
- Brain Connectivity
Project Title
Toward a Virtual Patient in Deep Brain Stimulation
Project Description
Deep Brain Stimulation – a highly efficacious treatment option for movement disorders such as Parkinson‘s Disease – is currently undergoing a paradigm-shift from stimulating local target regions toward network stimulation, i.e. neuronal modulation of distributed brain net- works. Specifically, it was long thought that the procedure exerts its therapeutic potential by local modulation of the target region itself. However, accumulating evidence suggests that effects on distributed brain networks and basal-ganglia-cortical loops are at least equally important. Our group published several articles of general network interactions between DBS electrodes and remote sites using electrophysiology and brain imaging. However, recently, in cooperation with Harvard Medical School, we were able to demonstrate that clinical DBS improvment may be predicted using MRI-based brain connectivity estimates between the site of stimulation and distributed cortical areas. In this study, the structural and functional connectivity profiles of DBS electrodes in 95 Parkinson patients from two DBS centers (Berlin & Würzburg) were highly predictive of clinical motor improvement across patients. Moreover, the study defined effective treatment networks for Parkinson‘s Disease that may one day be used to guide programming and targeting of deep brain stimulation after further validation. The technique was introduced for Parkinson‘s Disease but could even be of stronger use in the case of Dystonia, where changes in stimulation parameters often lead to a delayed symptom alleviation and guidance from computer models could be even more helpful in clinical practice. Adopting the technique for treatment in Dystonia is the current focus of our work.
PD Dr. med. Petra Hühnchen
Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology
Email: petra.huehnchen@charite.de
Fields of Research
- Chemotherapy
- Cell Death
- Neuroprotection
Project Title
Pathomechanisms and Prevention of Post-Chemotherapy Cognitive Impairment
Project Description
Neurotoxic phenomena are among the most common side effects of chemotherapy and often result in a major limitation for therapy, preventing optimal medical care. Furthermore, they significantly increase the burden of disease for cancer patients by severely affecting the quality of life. Changes of cognitive function associated with chemotherapy (post-chemotherapy cognitive impairment (PCCI) or »chemobrain«) have gained increased scientific interest, as the underlying pathophysiology remains unclear. We have gathered evidence that very low dosages of systemic chemotherapy such as paclitaxel or bortezomib are sufficient to induce cell death in adult neural stem cells via calcium and caspase-mediated pathomechanisms. This results in an impaired hippocampal neurogenesis and distinct cognitive deficits in mice. For paclitaxel, we have identified a molecular target and established an interventional strategy using lithium to inhibit cytotoxicity of adult neural stem cells in vitro and prevent cognitive impairment in vivo. In a translational effort, we are currently testing patients with paclitaxel chemotherapy for neurocognitive deficits in a prospective longitudinal study (CICARO-study) and comparing the results to non-treated patients. To further elucidate the underlying pathomechanisms of PCCI, we are investigating the role of proinflammatory cytokines in cell culture and animal models as well as patients to establish potential biomarkers. Furthermore, we are characterizing the functional outcome of newly identified molecular targets and evaluating novel therapeutics in the prevention of PCCI in animal models, gathering information for a potential clinical use.
Dr. med. Philipp Jakob
Charité – Universitätsmedizin Berlin, Department of Cardiology
Email: philipp.jakob@charite.de
Fields of Research
- Regeneration
- Cardiomyocytes
- High‐Throughput Screening
Project Title
Identification of Pro-Proliferative MicroRNAs in Human Cardiomyocytes Using a Functional High-Throughput Screening
Project Description
The project aims to detect microRNAs (miRNAs) with the ability to induce and enhance proliferation in human cardiomyocytes (CM) by using high-throughput screenings and high-content imaging techniques. MiRNAs are small non-coding RNAs, which profoundly alter protein output by interfering with messenger RNAs (mRNA) at the post-transcriptional level. In humans, CM withdraw- al from cell cycle is observed early after birth. The marginal number of adult CMs (approx. 1%) undergoing cell cycle and stem/progenitor cells supporting myocardial regenerative processes cannot compensate for a myocardial loss after cardiac injury. Therefore, the project aims to improve cardiac regeneration in patients with myocardial infarction/ischemic cardiomyopathy by targeting miRNAs significantly involved in cardiomyocyte pro-proliferative pathways. High-throughput-screenings using a miRNA-library were performed in CMs derived from human induced pluripotent stem cells (hiP- SC-CMs). Proliferative capacity of miRNA-transfected hiPSC-CMs was analyzed using a high-content imaging system. Significant miRNAs will be validated in vitro and in vivo. The project is performed in collaboration with the screening unit of Dr. J. P. von Kries (FMP, Berlin-Buch) and the stem cell group of Dr. K. Streckfuß-Bömeke (Universitätsmedizin Göttingen) and is supported by German Centre for Cardiovascular Research (DZHK) and Deutsche Stiftung für Herzforschung (DSHF).
Cao Zhong Jing Jin
Charité - Universitätsmedizin Berlin, CC08 - Chirurgische Klinik (CVK)
Email: cao.jin@charite.de
Fields of Research
- high-grade pancreatic duct dysplasia
- single-nuclei RNA sequencing
- spatial transcriptomics
Project Title
Deciphering the molecular determinants for the transformation of high-grade pancreatic duct dysplasia to invasive carcinoma by single-cell transcriptomics
Project Description
Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal abdominal cancers in humans. Despite significant progress in understanding the molecular mechanisms during pancreatic carcinogenesis, we still lack effective biomarkers for earlier detection or even targeted therapies. Recent advances in Single Cell Transcriptomics enable analyses of high-resolution RNA profiles on singled cells. These studies mainly focused on PDAC biology, while we predict that the analysis of the premalignant neoplasms may provide more important insights into the process of developing invasive pancreatic carcinoma.
Methods: In this study we analyze fresh-frozen pancreatic tissues harboring carcinoma with concomitant precursor lesions of high-grades and subsequently extract and sort the single nuclei for snRNAseq (single-nuclei RNA Sequencing). The cohort will include 10-12 tissues from 9-10 patients, who underwent resection of the pancreas for worrisome or malignant features. We have established an interdisciplinary workflow that will enable us the generation of high-profile transcriptomic signatures of cellular subpopulations involved in the carcinogenic process. The generated transcriptomic data will be correlated with spatial information using NanoString technologies (GeoMx) of cryosectioned tissue samples.
Preliminary Results: We have prospectively collected fresh frozen pancreatic tissue samples from 122 patients. On the selected samples, we have established and successfully applied an optimized workflow from tissue collection, histological sectioning, RNA extraction with quality assessment to library preparation and snRNA sequencing. Additionally, we were able to generate our first spatial transcriptomic data of representative pancreatic samples by GeoMx analyses, after defining regions of interest (ROI) and staining with cellular markers for subsequent spatial sequencing.
Conclusions: By combining two of the most sensitive and accurate technologies for transcriptional profiling, including snRNAseq and Spatial Transcriptomics, precious unbiased molecular data on rare entities of pancreatic precursor lesions and its neighboring carcinoma, will be obtained. Our particular focus on precursor lesions concomitant with carcinoma (PDAC), likely leads to novel insights into disease-relevant subpopulations and driving signatures (mRNA) during the pancreatic
cancer progression from high-grade to invasive carcinoma.Dr. med. Martin Jonczyk
Dr. med. Reiner Jumpertz-von Schwartzenberg
Charité – Universitätsmedizin Berlin, Department of Endocrinology and Metabolic Diseases
Email: reiner.jumpertz@charite.de
Fields of Research
- Obesity and Energy Balance Regulation
- Human Gut Microbiota
- Glucose Metabolism
Project Title
Plasticity of the Human Gut Microbiota during Weight Loss and its Consequences in Humanized Gnotobiotic Mice
Project Description
This project is geared towards understanding the complex constitution of commensal gut microbes in patients with metabolic diseases and their plasticity during weight loss. During the last years, we collected stool samples from overweight and obese individuals during a randomized weight loss intervention trial. To investigate gut microbial communities we performed 16 S sequencing and whole genome sequencing of the gut microbiota. We found substantial plasticity in the weight loss group with profound changes in the relative abundances of specific microbial clades that have been linked to metabolic health. These changes go along with gene content variation indicating a shift in the metabolic propensity of the of ‘obese-type’ microbiota. To test whether these changes themselves are relevant in body weight regulation we performed humanization experiments in germ-free mice. For this, we chose to transplant the gut microbiota of obese individuals before and after severe weight loss. Out preliminary data suggest that humanized mice receiving the gut microbiota from individuals after/during severe weight loss develop a dramatic weight loss within a very short period after transplantation, a phenomenon which is not seen in mice receiving the microbiota of the same individuals before weight loss. Additionally, just looking at the gut microbiota we were able to develop a machine learning algorithm that predicts weight loss during a weight loss program only based on the gut microbial composition at baseline. In a next step, we want to find the top microbial candidates that may promote negative energy balance and initiate the translation into a first human intervention trial.
Dr. med. Michael Kaczmarczyk
Charité – Universitätsmedizin Berlin, Charité – Universitätsmedizin Berlin, Department of Psychiatry and Neurosciences
Email: michael.kaczmarczyk@charite.de
Fields of Research
- Cognitive function
- Affective and stress-related disorders
- Psychoendocrinology
Project Title
Influence of hormones on depressive, stress-related, and anxiety disorders
Project Description
Traumatic experiences and adverse life events are risk factors for numerous somatic and mental disorders. Stress- and trauma-related disorders such as depressive and posttraumatic stress disorder are associated with sex-specific differences. Following traumatic experiences, women show higher prevalence rates, as well as higher symptom severity and comorbidity rates. In our previous
work we could show that both major depressive and posttraumatic stress disorder are associated with changes in cortisol and catecholamine metabolism, and that early life adversities are associated with cognitive impairments in later life. Fear conditioning is a crucial concept of learning theory, and is frequently applied to explain the development and maintenance of mental disorders. Increasing evidence suggests a pivotal role of sex hormones in fear conditioning, thus offering a possible explanation for sex-related differences. Preclinical studies, using techniques such as assessing
endogenous hormone levels or by pharmacologically blocking target receptors, have shown associations between estrogen and progesterone levels and cognition. Less is known about the effects of sex hormones on cognition in humans. Therefore, we systematically investigate the effects of
hormones on cognitive processes in depressive, stress-related and anxiety disorders.Dr. Michael Kaczmarczyk
Charité – Universitätsmedizin Berlin, Department of Psychiatry
Email: michael.kaczmarczyk@charite.de
Fields of Research
- Major Depressive Disorder
- Neuroenhancement
Project Title
Effects of Mineralocorticoid Receptor Stimulation on Cognitive Bias and Social Cognition in Patients with Major Depression: What Is the Role of NMDA Receptors?
Project Description
People suffering from major depression often show impaired cognitive function while cortisol secretion is increased. The steroid hormone cortisol is released in response to stress and acts in the central nervous system upon glucocorticoid (GR) and mineralocorticoid receptors (MR). GR are widely distributed across the brain while MR are predominantly expressed in the hippocampus and prefrontal cortex – two brain areas closely related to cognitive function and cortisol secretion. We have shown that fludrocortisone, a mineralocorticoid receptor agonist, improves memory and executive function in depressed patients and healthy controls. Stimulation of MR might have led to an increase of glutamate that acts on glutamatergic NMDA receptors in the hippocampus and prefrontal cortex. However, depressed patients not only exhibit cognitive deficits in traditional neuropsychological domains such as memory or executive function. In addition, there are depression-specific alterations such as cognitive bias and deficits in social cognition, two clinically highly relevant areas. Therefore, the specific aims of our work are two-fold: 1) To examine whether beneficial effects of fludrocortisone in depressed patients can be extended to depression-specific cognitive bias and to social cognition and 2) to determine whether beneficial effects of fludrocortisone depend on NMDA receptor function and whether these beneficial effects can be enhanced by co-administration of the partial NMDA receptor agonist D-cycloserine. Our study not only advances current knowledge by further examining the mechanism of action by which MR stimulation exerts beneficial effects on cognition but extends these effects to depression-specific cognitive bias and alterations in social cognition. Furthermore, a potential interaction between MR and NMDA receptors is highly clinically relevant given the promising results with NMDA receptor antagonists in the treatment of major depression.
PD Dr. med. Johannes Frederik Kahn
Charité – Universitätsmedizin Berlin, Department of Radiology (including Pediatric Radiology)
Email: johannes.kahn@charite.de
Fields of Research
- Computed Tomography
- Magnetic Resonance Imaging
Project Title
Iterative Reconstruction in Computed Tomography – Reducing Dose Not Image Quality
Project Description
Various novel technical solutions are subsumed under the term of iterative reconstruction (IR). Its goal is the efficient reduction of image noise and radiation dose in computed tomography (CT). The objective of this project is to investigate whether iterative reconstruction allows for an effective reduction of dose without having to accept a significant loss of image quality. The use of first-generation iterative image reconstruction techniques (ASIR) allows for a dose reduction of about one third compared to conventional filtered back projection (FBP) image re- construction while maintaining image quality. Particularly young patients who often receive multiple follow-up CT
exams may benefit from this reduction. To define more individualized and dose optimized CT examination protocols, additional patient populations need to be studied. In a next step, the previous research on radiation dose reduction and image optimization is to be continued and expanded in studies at the institute’s own research CT. It would be a milestone in CT diagnostic imaging if the expected dose values in the sub-millisievert range together with a corresponding good image quality turn out to be realistic.Dr. med. Jakob Kaminski
Charité – Universitätsmedizin Berlin, Department of Psychiatry and Psychotherapy
Email: jakob.kaminski@charite.de
Fields of Research
- Neuroscience
- Cognition
- Schizophrenia
Project Title
Investigating Learning and Cognition
Project Description
My workgroup investigates underlying neurobiological mechanisms that lead to impaired learning and neurocognitive processes in neuropsychiatric diseases. We apply a broad range of techniques in order to elucidate neurobiological underpinnings of complex human traits. We investigate large cohorts and estimate differential contributions of brain structure, function as well as genetic and epigenetic contributions to cognitive capacity. We explore malleable biomarkers for interindividual differences in cognitive abilities. We apply state-of-the-art in-vivo imaging techniques using functional magnetic resonance imaging (fMRI) and positron emission tomography (PET). More precisely, I am interested in the pathophysiology of psychosis and the mesocortical dopamine system that modulates putative glutamatergic prefrontal functions like working memory. I have a particularly strong commitment to translating my increasing methodological knowledge towards clinical application. In my research, I focus on alterations in neurocognitive processes using non-invasive brain stimulation (NIBS) techniques such as transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS). Non-invasive stimulation techniques are a putative therapeutic tool for several kinds of symptoms. The understanding of the effect of non-invasive stimulation techniques will help to refine the application. I am investigating the expermental modulation of brain activation and its impact on behavioral and neurobiological outcome measures like local activity (fMRI) and effective connectivity (dynamic causal modeling, DCM). DCM is an approach that over- comes the challenge of missing mechanistic insight. DCM exploits generative models that provide parameters which explain how the measured data could have arisen from neurophysiological mechanisms like task-dependent synaptic connectivity between neuronal populations. Taken together my current work is focusing on the exploration of interindividual differences in cognitive capacity which allow possible interventions that are capable of inducing changes in network processing in the human brain.
Dr. med. Jakob Kaminski
Charité – Universitätsmedizin Berlin, Department of Psychiatry and Neurosciences
Email: jakob.kaminski@charite.de
Fields of Research
- Neuroimaging
- Cognitive Neuroscience
- Schizophrenia
- Clinical Psychiatry
Project Title
The Neurobiology of Psychotic Disorders
Project Description
My research focuses on severe psychiatric diseases. I am investigating underlying neurobiological mechanisms that lead to impaired learning and neuro-cognitive processes in neuropsychiatric diseases. We apply a broad range of techniques in order to elucidate the neurobiological underpinnings of complex human traits. We investigate large cohorts and estimate differential contributions of brain structure, function as well as genetic and epigenetic contributions to cognitive capacity. We explore malleable biomarkers for interindividual differences in cognitive abilities. We apply state-of-the-art in-vivo imaging techniques using functional magnetic resonance imaging (fMRI), magnetic resonance spectroscopy, and positron emission tomography (PET). More precisely, I am interested in the pathophysiology of psychosis and the mesocortical dopamine system that modulates putative glutamatergic prefrontal functions like working memory. I have a particularly strong commitment to translating my increasing methodological knowledge towards clinical application. However, clinical phenotypes in psychiatric diseases are very heterogeneous and imaging techniques, thus far, only provide a limited explanation for this heterogeneity. Clinical characterization is still the gold standard, Therefore I started a new project evaluating the clinical use of patient-reported
outcomes both for clinical and research purposes. The upcoming use of recording patient-reported outcomes longitudinally might inform future studies and thus elucidated the aforementioned neurobiological mechanisms.Tabea Kao
Charité-Universitätsmedizin Berlin, Institut für Radiologie und Kinderradiologie (CVK)
Email: tabea.kao@charite.de
Fields of Research
- Interventional Oncology
- Hepatocellular Carcinoma
- Immune-Checkpoint Inhibitors
Project Title
Neoadjuvant Immunotherapy combined with Cryoablation in a Mouse Model of HCC
Project Description
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the fourth leading cause of cancer-related deaths worldwide. In recent years, immune checkpoint inhibitors such as Nivolumab, an anti-PD-1 agent, have emerged as a promising approach for the treatment of advanced stage HCC by preventing tumor immune escape. Similarly, cryoablation is gaining popularity as a minimally-invasive image-guided treatment for early stage HCC. Cryoablation is a form of local ablation based on repetitive freeze-thaw cycles that causes cell death through intracellular ice crystal formation. Currently, immunotherapy is only used in an adjuvant setting, and cryoablation still has a recurrence rate of about 20%. The combination of these two therapies is not yet used in clinical practice. This project aims to investigate the effect of neoadjuvant immunotherapy with anti-PD-1 combined with cryoablation on the tumor microenvironment and immune cell infiltration in a TIB-75 mouse model of HCC.
The study utilizes an orthotopic TIB-75 tumor model of HCC in BALB/c mice, which are divided into four groups: control, cryoablation only, anti-PD-1 only, and anti-PD-1 followed by cryoablation. After 7 days of tumor growth, immunotherapy is administered for a total of 3 doses for 7 days, immediately followed by cryoablation. Tumor samples are analyzed for immune cell infiltration and changes in the tumor microenvironment using immunohistochemistry and flow cytometry.
The hypothesis is that administering anti-PD-1 as neoadjuvant immunotherapy primes the TIB-75 murine HCC model for subsequent cryoablation and can alter the tumor microenvironment towards a more pro-inflammatory phenotype. Therefore a stronger intratumoral infiltration of T-cells after ablation is expected.Dr. med. Julia Kase
Charité – Universitätsmedizin Berlin, Medical Department, Division of Hematology, Oncology and Tumor Immunology
Email: julia.kase@web.de
Fields of Research
- Chemoresistance
- Aggressive B‐Cell Lymphomas
- Transgenic Mouse Models
Project Title
A Pan-Omics Approach to Treatment Failure in a Transgenic Mouse Model of Aggressive B-Cell Lymphomas
Project Description
Treatment failure is the key determinant of poor outcome in lymphoma therapy. Unveiling the underlying molecular mechanisms is critical to overcome drug insensitivity and may direct the development of novel therapies. Since patient samples are rarely available as matched pairs at diagnosis and at a resistant state, and cannot be further drug-challenged or subjected to functional validation experiments, we considered transgenic mouse models of cancer as valuable tools for the molecular dissection of treatment responsiveness. We utilize transcriptomics, proteomics, metabolomics, kinomics, whole exome sequencing and copy number analysis in a »pan-omics« approach to decipher mechanisms of treat- ment resistance in a Myc-driven lymphoma mouse model with previously documented cross-species predictability for human diffuse large B-cell lymphomas. Immunocompetent recipient mice were transplanted with primary Eμ-myc transgenic mouse B-cell lymphomas, and exposed to cyclophosphamide (CTX) upon tumor manifestation. Mass spectrometry-based proteomics, metabolomics as well as array-based transcriptomics, genomics, kinomics and copy number alteration analysis were applied, and the data subjected to bioinformatics processing to unveil mechanisms of treatment resistance. After treatment of lymphoma-bearing mice, lasting remissions (reflecting cure) were observed in about half of them. Repetitive treatments of mice harboring relapse lymphomas result- ed in progressively shortened remission times and finally led to full-blown resistance, thereby recapitulating clinical courses of patients with drug-insensitive aggressive lymphomas. Gene-, RNA-, protein- and metabolite-analyzing omics technologies were applied to compare curable vs. relapse-prone and resistant lymphomas, all with or without an additional short-term exposure to CTX to acutely challenge drug-specific response programs. Eμ- myc lymphoma-bearing mice treated in a clinical trial-like fashion were established as a versatile model of clinical chemoresistance. Going beyond a transcriptome-restricted investigation, our pan-omics strategy aims to dissect underlying mechanisms that will be further exploited as targets on their own for novel lesion-based therapies in future cancer precision medicine.
Prof. Dr. med. Johannes Keller, PhD
Charité – Universitätsmedizin Berlin, Center for Musculoskeletal Surgery
Email: johannes.keller@charite.de
Fields of Research
- Traumatic Brain Injury and Fracture Healing
- Polytrauma and Sepsis
- Bone Metabolism
Project Title
Cellular and Molecular Characterization of Fracture Healing in Traumatic Brain Injury
Project Description
Impaired fracture healing including malunions still represents an ongoing clinical challenge as treatment options remain limited. This is surprising since bone is one of two organs that is capable to completely restore structure and function without scar tissue formation. In contrast to healing impairments, the clinical phenomenon of traumatic brain injury (TBI) positively affecting fracture healing is of utmost importance from a basic science and clinical point of view. Using an experimental approach, we could previously demonstrate that callus formation is increased in a mouse model combining surgically induced TBI and fracture of the femur. As the underlying mechanisms remain unclear, we are currently investigating the cellular and molecular basis for the observed phenomenon. First, based on our own preliminary experiments and observations made by other investigators, we test the mechanistic involvement of leptin and alpha calcitonin gene-related peptide, both of which are elevated in poly-traumatized patients, in the increased callus formation following brain injury. In parallel, extensive gene expression profiling, histological and FACS analyses, as well as serum and urine measurements, are applied to further dissect and identify crucial target organs, cells and signaling events involved in accelerated fracture healing during TBI. Promising candidates and signaling pathways are further investigated using primary cell cultures and cell lines. Finally, pharmacologic and genetic proof-of-principle experiments are performed to verify the influence of established candidates in vivo. The cellular and molecular characterization of accelerated fracture healing-complementing research on delayed healing is the basis for a fundamental understanding of bone healing and its challenges, and backbone to any development of new therapeutic strategies for affected patients.
Dr. med. Marcus Kelm
Charité – Universitätsmedizin Berlin, Department of Pediatric Cardiology and Congenital Heart Disease
Email: mkelm@dhzb.de
Fields of Research
- Digital Medicine and Data Science
- Congenital Heart Disease
- Cardiovascular Imaging
Project Title
Decision Support System for Structural Heart Disease
Project Description
Surgical and catheter-based treatment procedures in acquired and congenital structural heart disease usually focus on normalization of hemodynamics (short term outcome), as well as longer term goals, including the restoration of normal arterial/myocardial function, exercise tolerance and absence of re-hospitalization. Advances in digital health and biophysical computational modeling allow performing virtual interventions that can predict short term hemodynamic outcome. However, it has remained diffi cult to predict how these immediate changes translate into mid/long term clinical outcomes. Machine learning that makes use of clinical routine measurements, sensor data and non-invasive imaging data have the potential to overcome this knowledge gap and predict important parameters of long term function, providing a Decision Support System that includes: (1) Virtual treatment procedures, which will be performed and validated against results from the actual clinical outcome in order to provide reliable and scalable solutions for future treatment optimization. (2) Computational biophysical models, in order to simulate immediate hemodynamic outcome (pressure gradients, fl ow profi les). (3) Machine learning techniques, to predict long term functional parameters (arterial blood pressures and myocardial function) and to provide realistic boundary conditions for longer-term biomedical models and virtual treatment. Non-invasive and imaging-based biomarkers, including internal myocardial power, circulatory effi - ciency, and aortic distensibility are, furthermore, evaluated to gain new insights into disease pathophysiology and individual disease response.
Dr. med. Martin Kenda
Charité – Universitätsmedizin Berlin, Department of Neurology and Experimental Neurology
Email: martin.kenda@charite.de
Fields of Research
- Hypoxic-Ischemic Encephalopathy
- Advanced Neuroimaging
- Neuroprognostication
Project Title
Quantification of regional Brain Tissue Water Uptake from Head-CTs after Cardiac Arrest
Project Description
The aim of this project is to identify and potentially validate a novel, easily accessible diagnostic and prognostic parameter for the reversibility of brain damage after cardiac arrest (CA) that could be used for outcome prediction and therapeutic interventions.
We will investigate comatose patients that had an initially successful resuscitation after CA in this multidiciplinary project in cooperation with the Department of Medical Intensive Care, the Department of Neuroradiology and the Department of Clinical Sciences at Lund University (Sweden).
Selective water uptake of neurons and brain tissue edema are key pathophysiological phenomena of hypoxic-ischemic encephalopathy (HIE) after CA. Although brain computed tomography (CT) is the most used tool to assess the severity of HIE, current guidelines only recommend measuring abnormalities within a single scan without considering changes over time. Recent studies quantifying net water uptake (NWU) in CT imaging of stroke patients have discovered thresholds for the reversibility of brain damage in focal lesions. The evolution of radiodensity in serial CT imaging could be used to quantify regional brain water uptake as a prognostic marker after CA. We aim to do this using an extended version of an algorithm for automated CT analysis from our previous work. We will investigate NWU for a variety of brain regions, and correlate it with neurological outcome and other biomarkers for HIE such as electroencephalography (EEG) and blood markers. For the validation of our results, we will be able to use data from a large international randomized multicenter trial on hypothermia after cardiac arrest (TTM2).
A successful project could facilitate future neuroprognostication through deriving relevant information from an already well-established diagnostic tool.Anton Kern
Charité - Universitätsmedizin Berlin, CC17 - Klinik für Pädiatrie m.S. Onkologie und Hämatologie (CVK)
Email: anton.kern@charite.de
Fields of Research
- CAR-T therapy
- pediatric oncology & hematology
- immunology
Project Title
Engineering CAR-T cells with a Fas-4-IBB switch receptor to overcome activation-induced cell death and improve CAR-T cell therapy for neuroblastoma
Project Description
Chimeric antigen receptor T (CAR-T) cell therapy, although highly effective against blood-borne malignancies, has not yet achieved major success in pediatric solid tumors such as neuroblastoma (NB). This is in part related to an immunosuppressive tumor microenvironment (TME) characteristic for solid tumors as well as tumor heterogeneity that frequently result in recurrence of tumor variants that have lost the target antigen . Additionally, the effects of the TME and the strong and repetitive stimulation of CAR-T cells when exposed to the tumor often result in exhaustion and even depletion of CAR-T cells called activation-induced cell death (AICD). Those effects result in lower quality and quantity of administered CAR-T cells limiting the effectiveness of
CAR-T cell therapy. This is especially interesting because clinical data suggests that prolonged persistence of CAR-T cells corelates with clinical outcome. Using more sophisticated CAR-T engineering to overcome AICD and to effectively prolong the survival of CAR-T cells could be the answer to transfer the great results seen in hematologic malignancies to patients with neuroblastoma and maybe even other pediatric solid tumors. My study aims to do so by developing CAR-T cells resistant to Fas-induced cell death, one of the main effector pathways of AICD, to save the strongly activated CAR-T cells from death mediated by the engagement of FasL expressed on T cells, neuroblastoma cells, or immune modulatory cells in the TME. To achieve that goal CAR-T cells will be engineered to express a switch receptor that makes them resistant to FasL-mediated killing by turning the death signal into a costimulatory signal.Dr. med. univ. Barbara Kern, PhD
Charité – Universitätsmedizin Berlin, Department of Surgery
Email: barbara.kern@charite.de
Fields of Research
- Vascularized Composite Tissue
- Allotransplantation
- Transplant Immunology
Project Title
Novel Treatment and Diagnostic Approaches Utilizing the Role of Dendritic Cells in Immune Responsiveness
Project Description
Vascularized composite tissue allotransplantation (VCA) including hand, upper extremity, face, and abdominal wall transplants have emerged from a visionary therapy option in the past to become an innovative reconstructive treatment modality for patients with devastating tissue defects that are not amendable for conventional treatment protocols (Swearingen et al, Transplantation 2008). However, patients must undergo life-long immunosuppression with unwanted effects such as infection, renal toxicity, and cancer. Therefore, it is crucial to understands the underlying mechanisms of skin rejection as the most immunogenic fraction of VCAs to improve existing immunosuppressive therapeutic approaches in VCAs. Our overall objective is, therefore, to critically examine the immunogenicity of mature and immature DCs. Of note, studies of DCs in VCA have also the potential to provide novel treatment approaches for skin and, ultimately, solid organ transplantation. Extremity transplants are currently challenged by two main unsolved problems: the speed of nerve regeneration to regain full motor and sensory function, and most importantly, the application of immunosuppressants with a myriad of unwanted and life-threatening complications for a non-life saving procedure (Shores et al, J Am Acad Orthop Surg, 20100. Dendritic cells (DC) are known to play a key role in T-cell activation via presenting antigenic peptides in the context of MHC molecules to the T-cell receptor (TCR), as well as by providing co-stimulatory signals required for T-cell proliferation and differentiation (Benichou et al, IImmunotherapy 2011). We hypothesize that intragraft DC composition plays a critical role in the potent immunogenicity observed in VCA.
Dr. med. Ahmed Abdelrahim Khalil
Charité – Universitätsmedizin Berlin, Department of Neurology and Experimental Neurology
Email: ahmed-abdelrahim.khalil@charite.de
Fields of Research
- Neurology
- Radiology
- Cerebrovascular disease
Project Title
Validation of a Non-Invasive, Automated Perfusion MRI Method in Stroke Patients
Project Description
Cerebrovascular diseases and stroke are some of the leading causes of morbidity and mortality worldwide. Understanding which pathophysiological mechanisms are responsible for perpetuating tissue damage in individual patients can help clinicians make better decisions about how to treat these patients. Much of this information is, however, unavailable to clinicians in routine practice because the methods used to assess these pathophysiological phenomena are inconvenient, unreliable, or inaccessible. As a result, more than two-thirds of stroke patients are not eligible for crucial treatments
in the very early stages of the disease, where the benefit of these treatments is highest. My research focuses on developing and validating neuroimaging techniques that are easier for clinicians to access, use, and interpret. The aim is to use these techniques to provide clinicians with individualized and readily interpretable information on stroke pathophysiology using efficient and convenient methods, which could potentially improve how, and how many, strokes are treated.Dr. med. Evelyn Kidess-Sigal
Charité – Universitätsmedizin Berlin, Medical Department, Division of Hepatology and Gastroenterology
Email: evelyn.kidess@charite.de
Fields of Research
- Circulating Tumor Cells
- Circulating Tumor DNA
Project Title
Evaluation of the Potential of »Liquid Biopsies« in Representing Mutational Profiles of Metastatic Tissue
Project Description
In order to administer an individually tailored therapy to a cancer patient, currently, a tumor is molecularly characterized by analyzing tissue biopsies. Unfortunately, the obtainment of tissue biopsies is invasive and therefore associated with a risk of complications, and in some cases may not even be possible due to difficult accessibility. Using Liquid biopsies is a promising alternative, as it requires solely obtaining blood samples, which can be molecularly analyzed. Up to now, it is unknown, to which extent the mutational profile of metastatic tissue can be revealed by analyzing Circulating Tumor Cells (CTCs) or Circulating Tumor DNA (ctDNA), and which of these liquid biomarkers is most representative when comparing different tumor entities. To answer this question, in the current project we are analyzing blood samples from patients suffering from colorectal cancer, head and neck cancer and malignant melanoma with distant metastases. Using a panel consisting of 327 genes frequently associated with cancer, blood and tissue samples are sequenced and the mutational profiles of CTCs and ctDNA are going to be compared to the ones in metastatic tissue as well as primary tumor tissue, if applicable. We strongly believe, that liquid biopsies have the potential to expand the diagnostic repertoire in cancer patients by enabling the obtainment of molecular data non-invasively. Thus, patients may significantly benefit from our results, since the analysis of liquid biopsies will enable the administration of tailored therapy for every individual patient corresponding to the molecular characteristics of the tumor.
Dr. med. Evelyn Kidess-Sigal
Charité – Universitätsmedizin Berlin, Medical Department, Division of Hepatology and Gastroenterology
Email: evelyn.kidess@charite.de
Fields of Research
- Circulating Tumor Cells
- Circulating Tumor DNA
Project Title
Evaluation of the Potential of »Liquid Biopsies« in Representing Mutational Profiles of Metastatic Tissue
Project Description
In order to administer an individually tailored therapy to a cancer patient, currently, a tumor is molecularly characterized by analyzing tissue biopsies. Unfortunately, the obtainment of tissue biopsies is invasive and therefore associated with a risk of complications, and in some cases may not even be possible due to difficult accessibility. Using Liquid biopsies is a promising alternative, as it requires solely obtaining blood samples, which can be molecularly analyzed. Up to now, it is unknown, to which extent the mutational profile of metastatic tissue can be revealed by analyzing Circulating Tumor Cells (CTCs) or Circulating Tumor DNA (ctDNA), and which of these liquid biomarkers is most representative when comparing different tumor entities. To answer this question, in the current project we are analyzing blood samples from patients suffering from colorectal cancer, head and neck cancer and malignant melanoma with distant metastases. Using a panel consisting of 327 genes frequently associated with cancer, blood and tissue samples are sequenced and the mutational profiles of CTCs and ctDNA are going to be compared to the ones in metastatic tissue as well as primary tumor tissue, if applicable. We strongly believe, that liquid biopsies have the potential to expand the diagnostic repertoire in cancer patients by enabling the obtainment of molecular data non-invasively. Thus, patients may significantly benefit from our results, since the analysis of liquid biopsies will enable the administration of tailored therapy for every individual patient corresponding to the molecular characteristics of the tumor.
Dr. med. Tina Kienitz
Charité – Universitätsmedizin Berlin, Department of Endocrinology and Metabolic Diseases
Fields of Research
- Androgens
- Endocrine Cancers
- Adrenals
Project Title
Androgen-Dependent Regulation of Whole Body Sodium Metabolism, Blood Pressure and Cardiovascular Function
Project Description
Nowadays, cardiovascular diseases greatly determine morbidity and mortality in industrialized countries. Epidemiological findings demonstrate sex differences in cardiovascular risk: In industrialized countries, men suffer from cardiovascular diseases more often and at a younger age than women [Gos-Wald A et al. Bundesgesundheitsblatt, Gesundheitsforschung Gesundheitsschutz 2013]. Men also have a higher blood pressure than women [Stamler J et al. JAMA 1976]. These observations suggest that androgens contribute to this sexual dimorphism. Sodium intake influences the development of arterial hypertension, as well [Elliott P et al. BMJ 1996]. However, the exact mechanisms responsible for salt-sensitive hypertension and the relationship between sex, salt intake and endogenous regulation of sodium metabolism are widely unknown. Experimental data provided compelling evidence that macrophages are key elements in the regulation of sodium accumulation in the skin [Machnik A et al. Nature Medicine 2009]. High sodium intake promoted lymph hyperplasia in rats. This effect was mediated via the tonicity-responsive enhancer binding pro- tein (TonEBP) in mononuclear phagocyte system (MPS) cells. TonEBP works as a transcription factor and enhances vascular endothelial growth factor C (VEGF-C) secretion. Interference with this system might contribute considerably to the development of sex-specific differences in blood pressure control. The androgen receptor (AR) is expressed in macrophages [Ikeda Y et al. J Endocrinol 2012]. In sum, the role of androgens in the regulation of whole-body sodium metabolism is only poorly understood. We generated macrophage/monocyte-specific androgen receptor knockout mice to investigate macro- phage-mediated androgen action. Since macrophages also play a role in the development of obesity, glucose and lipid metabolism will be explored in this mouse model, as well.
Dr. med. Arne Kienzle
Charité – Universitätsmedizin Berlin, Center for Musculoskeletal Surgery
Email: arne.kienzle@charite.de
Fields of Research
- Bone Metabolism
- Joint Infection
- Osteitis
- Arthroplasty
Project Title
Role of Osteitis and Osteomyelitis in Altered Bone Homeostasis in Patients with Periprosthetic Joint Infection
Project Description
Despite increased use of antibiotics and improved aseptic surgical techniques, periprosthetic joint infections (PJI) still occur in 1-5% of primary total knee arthroplasties. In PJI, microorganisms form a biofilm on the implant making the infection highly resistant to antibiotic treatment. Once a biofilm forms on the implant, complete removal of the infected prosthesis and, in most cases, in a second stage surgery, reimplantation of a new prosthesis is necessary. After PJI-dependent revision surgery, we found a drastically elevated risk for prosthesis failure: In this study, 22% of all patients suffered from long-term complication aseptic loosening and 16% from recurrent PJI; suggesting PJI significantly and lastingly alters the bone metabolism. Our research focuses on understanding the altered pathomechanisms involved in this pathology. We hypothesize that the increased risk for aseptic loosening after PJI is due to an inflammatory response in the bone and bone marrow, i.e. osteitis and osteomyelitis. In PJI, adaptive immunological processes potentially impact the regenerative function of osteoblasts and thus disturb the bone and bone marrow homeostasis, subsequently altering bone density and metabolism. Our clinical observations suggest that these changes persist despite guideline compliant anti-microbial and surgical treatment. In this respect, affected patients could benefit from treatments that restore bone homeostasis and counteract osteitis and bone loss. Additionally, profiling patient’s systemic immune competence from peripheral blood samples may help identify patients especially at risk for impaired bone formation and thus consecutive prosthesis failure.
PD Dr. med. Konrad Klinghammer
Dr. med. Samuel Knauß
Charité – Universitätsmedizin Berlin, Department of Neurology and Experimental Neurology
Email: samuel.knauss@charite.de
Fields of Research
- Digital Health
- Global Health
- Health Economics
Project Title
mTOMADY – Building Digital Technology to Provide Access to Quality, Affordable Essential Healthcare
Project Description
Out-of-pocket payments (OPP) remain the predominant mode of healthcare fi nancing in many low and middle-income countries (LMICs). However, the costs for skilled care frequently exceed the savings or assets which can be accessed at one time by a low-income household, leading to medical impoverishment. Today, more than 70% of worldwide mobile phone subscriptions come from LMICs with more than 74 subscriptions per 100 people in Sub-Sahara Africa (SSA) in 2016. In the footsteps of this revolution have followed mobile payment systems, colloquially known as Mobile Money (MM), which commonly utilize low-tech systems to enable fi nancial transactions without the need for a bank account. Making use of this technological development, MM-based hospital insurance or savings mechanisms, which enable low-income households to set aside funds exclusively for healthcare, have been introduced successfully in several SSA countries. However, a substantial knowledge gap remains on the impact, performance, and economic costs of MM-based healthcare fi nancing mechanisms. By building on existing mobile money infrastructure, we have developed and implemented a mobile-phone-based digital savings and payment platform, the Mobile Health Wallet (MHW), for skilled healthcare during pregnancy and delivery. The MHW is a closed loop system enabling expectant mothers to save, send, receive and pay money exclusively for healthcare. We hypothesize that the MHW will improve access to skilled care during pregnancy and childbirth by reducing fi nancial obstacles. To test this hypothesis, we designed a cluster randomized controlled trial, called the Mobile MOney for maTernal HEalthcare Related Spending (4MOTHERS) trial for implementation of the MHW in public health facilities in Antananarivo, the capital of Madagascar. In particular, we will adopt a multidisciplinary, mixed-methods approach to assess three components of the MHW intervention: i) its impact, by measuring usage of public health facilities and health outcomes; ii) its performance, by measuring adoption, usage and user satisfaction; and iii) its economic cost, by measuring incremental costs of the intervention per pregnancy and model the cost-effectiveness of the intervention. We expect the results of our study to guide future initiatives and health policy decisions related to financial risk protection and universal healthcare coverage through digital technology in Madagascar and other low and middle income countries.
Prof. Dr. med. Stephan Köhler
Charité – Universitätsmedizin Berlin, Department of Psychiatry and Psychotherapy
Email: stephan.koehler@charite.de
Fields of Research
- Affective Disorders
- Chronic Depression
- Psychotherapy Research
Project Title
Neurobiology of Chronic Depression: Alterations in Emotion Regulation and Influence of Psychotherapy
Project Description
About 20% to 30% of patients with a major depressive dis- order (MDD) have a chronic disease course (MDD lasting for at least two years). Chronic depression (CD) is a specific subtype of MDD, however, it is barely characterized and demonstrates with high rates of treatment resistance. In contrast to episodic depression, CD often has an »early onset« even in adolescence. The development and persistence of CD are often related to adversity and maltreatment experienced during childhood as emotional neglect for example. Patients with CD often demonstrate a »lack of social empathy«, interpersonal challenges, global and prelogical thinking processes and additionally a reduced affective control. Furthermore, there is growing evidence for a disturbed emotion regulation in patients with depression, however, the results are inconsistent. Especially early childhood trauma seems to be associated with an altered activity of emotion-regulating brain regions (increased amygdala activity, reduced activity of prefrontal cortex). In our project, we want to evaluate, if emotion regulation (reappraisal) is altered in CD in contrast to episodic depression in a fMRI paradigm. Furthermore, we want to investigate, if emotion regulation is depending on specific emotional activation and if there is an altered regulation of the amygdala and the prefrontal cortex. The influence of a specific psychotherapy on emotion regulation in CD is part of a third project.
Dr. med. Leif Torben Koschützke
Charité – Universitätsmedizin Berlin, Department of Neurology and Experimental Neurology
Email: leif.koschuetzke@charite.de
Fields of Research
- Motor rehabilitation
- Stroke
- Optogenetics
- Deep Brain Stimulation
Project Title
Neural Mechanisms of Motor Recovery After Stroke
Project Description
Stroke is one of the most common diseases with acute onset. It is considered to be among the leading causes of disability worldwide, resulting mainly from remaining motor deficits. There are a lot of efforts to improve emergency care and early rehabilitation with notable improvement in the therapies for stroke patients. However, little is understood regarding the cellular mechanisms of motor recovery after stroke especially in patients who are severely disabled. Studies and previous experiments hint at the neurotransmitter serotonin to play an important role in the recovery of motor deficits. We hypothesize that an increase in serotonergic transmission in the surroundings of the brain tissue affected by stroke (penumbra) will improve the motor deficits. In our methodological approach we are using different state-of-the-art technique to examine and modulate the serotonergic system in mice, e.g. with chemogenetic, optogenetic and electric stimulations. Furthermore, we are expecting to show improvement of motor recovery and be able to identify the critical parts of the serotonergic system using those modulations and immunohistological analyses. These experiments have to be considered as groundwork in the understanding of underlying mechanisms of longterm rehabilitation after stroke and can possibly contribute to the refinement of rehabilitation paradigms.
PD Dr. med. Alexander Kowski
Dr. med. Matteus Krappitz
Univ.-Prof. Dr. med. Peter Krawitz
Charité – Universitätsmedizin Berlin, Institute of Medical Genetics and Human Genetics
Email: pkrawitz@uni‐bonn.de
Fields of Research
- GPI‐Anchor Deficiencies
- Bioinformatics
- Interpretation of Whole Genome Sequences
Project Title
Systematic Analysis of Genotype-Phenotype Correlations in GPI-Anchor Deficiencies
Project Description
In all eukaryotes, there is a complex in the plasma membrane with the key task of anchoring glycoproteins on the cell surface, called the glycosylphosphatidylinositol anchor (GPI-anchor). GPI-anchored proteins (GPI-APs) play a central role in signal transduction, cell adhesion, and antigen presentation. Defects in the synthesis and maturation of the GPI-anchor and their consequences for GPI-APs represent a class of congenital disorders of glycosylation (CDG) that can cause congenital as well as acquired disorders. Among the inherited forms is Mabry syndrome, a recessive disorder that is characterized by intellectual disability, epilepsies, an elevated alkaline phosphatase and a distinct facial gestalt. Paroxysmal nocturnal hemoglobinuria, PNH, is an acquired GPI-anchor deficiency, due to somatic loss of function mutations in cells of the myeloid lineage. Currently, about 30 genes are known to play a role in the GPI-anchor synthesis and maturation. In several of these genes, disease-causing mutations could be identified over the recent years. We found pathogenic mutations in the genes PIGV, PIGO, PGAP2 and PGAP3 in patients with Mabry syndrome and mutations in PIGT in patients with atypical PNH for the first time. In our project, we aim at identifying novel genes that are involved in the GPI pathway as well as regulatory mutations. For this purpose, we use exome sequencing and whole genome sequencing to find pathogenic mutations in patients with suspected GPI-anchor deficiencies of the unknown molecular cause. Flow cytometric analyses play a key role in the assessment of suspected GPI-anchor deficiencies and bioinformatics are an essential part of the data evaluation.
PD Dr. med. Felix Krenzien
Charité – Universitätsmedizin Berlin, Department of Surgery
Email: felix.krenzien@charite.de
Fields of Research
- Liver Regeneration
- Liquid Biopsy
- Differentiation of T‐Cells
Project Title
New Regulators of Liver Regeneration
Project Description
Primary and secondary malignancies of the liver represent the second most common cause of cancer deaths worldwide. It is well established that liver surgery is oncologically superior to systemic therapy and locoregional treatment alternatives in primary liver malignancies. Evolving evidence even suggests liver resection increase survival rates in patients with localized tumor spread. Thus, extended liver resections are increasingly applied to a broader spectrum of patients, e.g. patients at a high age or with impaired regeneration capacities due to underlying chronic liver disease, e.g. non-alcoholic fatty liver disease (NASH). Preoperative possibilities to dissect patients who benefit from liver surgery from patients who will face serious complications, e.g. postoperative liver failure, are still limited. Therefore, a better understanding of liver regeneration and non-invasive diagnostic are urgently needed, as it would help to increase the safety of liver surgery and to offer liver resection to a higher number of critically ill patients. The objective is to gain a better understanding of liver regeneration and to dissect patients already preoperatively, who will suffer from primary and secondary liver cancer. The anticipated findings may allow diagnosis of liver tumors well in advance and help to avoid acute or acute on chronic liver failure.
Dr. med. Jakob Kreye
Charité – Universitätsmedizin Berlin, Department of Pediatric Neurology
Email: jakob.kreye@dzne.de
Fields of Research
- Neuroscience
- Neuroimmunology
- Humorla Immune Response
Project Title
Evaluation of Humoral Cross-Reactivity to Viral Antigens and Central Nervous Autoantigens in Encephalitis
Project Description
Encephalitis is a rare but serious disease with neurological dysfunction in the context of inflammation of the brain parenchyma, with a disease peak in infancy with 13.5 cases per 100,000. While the causal clarification remains unclear in over 30% of the cases, two main forms can be distinguished in the other cases. On the one hand, primarily infectious encephalitis occurs as a result of direct invasion of the central nervous system (CNS) by a pathogen, usually neuroinvasive viruses, most commonly herpes simplex viruses. On the other hand, auto-antibodies can cause so-called autoimmune encephalitis (AIE) as part of an aberrant immune reaction, such as anti-NMDA receptor encephalitis. AIE is more likely to be associated with viral infections, best shown for AIE after herpes simplex encephalitis (HSE), which typically occurs two months after viral infection in 27% of Anti-NMDA receptor antibodies can be detected in about two thirds of these patients a phenomenon that has been shown in a similar manner after experimental HSV infections in a mouse model. However, the mechanisms underlying AIE after HSE have so far remained
largely unclear. Increased titers of serum HSV antibodies were found in patients with NMDA receptor encephalitis without clinical HSE, possibly hinting towards a molecular mimicry as a trigger of autoantibody production. But also around a third of post-HSE patients also develop auto antibodies against other neuronal. In addition, AIEs have also been described in association with other viral infections, which suggests general trigger factors. Further studies are therefore necessary to understand the host and environmental factors that lead to the production of autoantibodies in patients after viral encephalitis. Using established methods in the recombinant generation and characterization of disease-specific antibodies from patients’ CSF or blood samples this project aims to expanded understanding of antibody-mediated neurological and psychiatric diseases, Do defined pathogenic autoantibodies from AIE patients (without a history of viral encephalitis) have cross-reactivities against viral targets?2. Can monoclonal antiviral antibodies be isolated from patients with viral encephalitis or AIE after viral encephalitis? Are reactivities against central nervous autoantigens detectable for these antiviral antibodies or other antibodies from the same patient sample?Dr. med. Daniel Kroneberg
Charité – Universitätsmedizin Berlin, Department of Neurology and Experimental Neurology
Email: daniel.kroneberg@charite.de
Fields of Research
- Parkinson’s Disease
- Movement Disorders
- Deep brain stimulation
- Gait assessment
Project Title
Network Modulation for the Improvement of Gait Function in Parkinson’s Disease
Project Description
Disturbances of gait and balance and specifically freezing of gait (FoG) are clinical features of advanced stages of Parkinson’s disease (PD) that are associated with an increased risk of falls, reduced mobility and impaired quality of life. Deep brain stimulation (DBS) of the subthalamic
nucleus (STN) is a highly efficacious treatment for motor symptoms of PD such as tremor, rigidity and bradykinesia but with limited effects on gait disability. Therapeutic effects of DBS relate to modulation of distinct brain networks connected to the stimulation area via basal-ganglia-cortical-pathways. Here, specific structural and functional connectivity patterns have been identified that are associated with and predictive of motor improvement. We will adapt this methodology to study the optimal connectivity profiles of DBS for improving gait function and particularly FoG in Parkinson’s disease. To account for the diversity of gait phenomena in PD, sensor based kinematic measurements will provide high resolution, multi-parametric assessments of gait performance ON and OFF DBS. For each patient, specific profiles of network activation and connectivity will be
modeled from the reconstructed DBS-electrodes based on normative structural and functional connectomes and then related to individual modulation of gait performance. This will clarify if we need to target different networks to treat gait disability in contrast to other motor symptoms of PD. This study aims to optimize DBS therapy towards a more patient- and symptom-oriented approach that may be integrated into future solutions for adaptive DBS.Dr. med. Dorothee Kübler
Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology
PD Dr. med. Dorothee Kübler-Weller
Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology
Email: dorothee.kuebler@charite.de
Fields of Research
- Cognition
- Neuropsychiatry
- Parkinson’s disease, movement disorders
Project Title
Predictors of Cognitive Decline after Deep Brain Stimulation in Parkinson’s Disease
Project Description
The course and severity of cognition in Parkinson’s dis-ease (PD) is of outstanding importance for our patients and their quality of life. When it comes to deep brain (DBS) stimulation surgery and chronic stimulation the cognitive prognosis is even more relevant. In a first ret-rospective study, I was able to show that the volume of the Ncl. basalis Meynert, the main cholinergic nucleus of the basal forebrain, is a significant predictor of cog-nition 12 months after DBS surgery. In order to take into the multifaceted etiology of cognitive change after DBS surgery, I set up and executed a prospective study includ-ing more possible predictors (https://clinicaltrials.gov/ct2/show /NCT03982953): Detailed preoperative pheno-typing regarding non-motor symptoms, imaging, demen-tia markers and genetics was conducted. An extensive tablet-based test battery specially tailored for and val-idated in patients of different stages of Parkinson’s dis-ease was applied prior to surgery as well as 3 and 12 months after. Additionally, perioperative procedures that can influence cognitive outcomes and the depth of nar-cosis via an intraoperative EEG were recorded. As post-operative delirium can lead to permanent cognitive deficits, screening for this complication was conducted three times daily. Preliminary results suggest that, in particular, age, dopaminergic dose, but also deficits in specific neuropsychologic domains influence the occur-rence and severity of a postoperative delirium which, in turn, has a negative impact on cognition 12 months after DBS surgery. The overarching goal of my research is to gather knowledge on the effects and risks of therapeutic strategies in movement disorders in order to guide patients to their individual personalized treatment with optimal and long-lasting effects.
Dr. med. Joseph Kuchling
Charité – Universitätsmedizin Berlin, Department of Neurology and Experimental Neurology
Email: joseph.kuchling@charite.de
Fields of Research
- Neurology
- Neuroimaging
- Neuroinflammation
Project Title
7 Tesla T2*-Weighted MRI Mapping in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorders
Project Description
Multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) are both neuroinflammatory diseases with overlapping clinical and paraclinical presentation. Despite the introduction of N MO-specific aquaporin-4-antibody (AQP4-ab) and quite recently myelin oligodendrocyte-glycoprotein-antibody (MOGab) into neurological diagnostic workup, accurate differential diagnosis in patients with acute and relapsing CNS inflammation still remains difficult. As a consequence, the different disease entities are still frequently misdiagnosed and existing effective therapy is withheld from a considerable number of MS and NMOSD patients. However, overt histopathological differences between MS, AQP4-NMOSD and MOG-NMOSD with particular regards to myelin content within and outside of lesion formations have been previously described. The advent of modern T2* MRI mapping techniques allows for MRIbased quantification of myelin content within brain tissue in vivo. By use of 7 Tesla MRI at ultrahigh field strengths, we further augment image contrast and myelin quantification accuracy of T2* sequences compared to conventional routine MRI at 3 Tesla. Therefore, we attempt to explore the potential of ultrahigh field MRI-based quantification of brain myelin content to differentiate multiple sclerosis (MS) from neuromyelitis optica spectrum disorders (NMOSD) by assessing quantitative T2* parameters within inflammatory lesions and in different brain regions apart from overt lesion sites. In our clinical study, we investigate patients with MS and antibody-associated NMOSD with regards to their
clinical and 7 T T2* MRI mapping features to evaluate sensitivity and specificity of T2* mapping to distinguish between MS and NMOSD. The ultimate goal is to not only visualize different myelin concentrations within brain tissue of different disease entities in vivo, but also to improve current MR differential diagnostic criteria to allow for early and accurate differential diagnosis for patients with neuroinflammatory diseases in a clinical setting.Dr. med. Anna Kufner
Charité – Universitätsmedizin Berlin, Department of Neurology and Experimental Neurology
Email: anna.kufner@charite.de
Fields of Research
- Ischemic stroke
- Magnetic resonance imaging (MRI)
- Contrast-enhanced MRI
Project Title
Training-Induced Changes in Vascular Morphology and Cerebral Perfusion after Stroke – a Multiparametric MRI Study
Project Description
Early rehabilitation is an essential part of the recommended therapy following an acute cerebrovascular event due to unequivocal evidence that regular physical activity not only mitigates risk factors (i.e. hypertension, dyslipidemia) but also has a beneficial effect on functional recovery following stroke. However the underlying mechanisms of physical activity leading to an improved outcome are poorly understood. Pre-clinical studies from our research group have demonstrated the beneficial effects of exercise on long-term stroke outcome in rodents and have attributed the observed effect to training- induced angiogenesis. Physical activity not only led to a histological increase in microvessel density but also led to visible changes in vessel morphology and ultimately resulted in enhanced cerebral flood flow and better long-term functional recovery in rodents following minor ischemic stroke. In patients, the mechanisms underlying the beneficial effects of exercise following stroke are far less explored. In 2013, our research group designed and initiated the PHYS-STROKE Trial (a Phase III randomized controlled trial [RCT]) – which was the first trial designed to assess the effect of physical activity on functional outcome following stroke. Recent developments in magnetic resonance imaging (MRI) suggest that selected sequences – such as vessel size imaging (VSI) – now allow for an in vivo assessment of cerebral microvasculature in patients. With this novel imaging technique in mind, an exploratory sub-study of the PHYSSTROKE trial was designed called BAPTISe (Biomarkers and perfusion – training induced change after stroke), in which a subgroup of patients receive multiparametric contrast-enhanced MRI before and after intervention (aerobic fitness vs. relaxation). The aim of the current project is to translate our own pre-clinical findings on the effects of exercise on cerebral perfusion and angiogenesis into clinical research with the use of multiparametric, contrast-enhanced MRI. The aim of this project is to assess whether VSI can reliably assess the cerebral microvasculature in-vivo in acute and sub-acute stroke patients. Furthermore, we aim to assess whether physical training will result in changes in MRI-derived microvascular morphology and cerebral perfusion parameters in stroke patients, corresponding to pre-clinical findings and whether these changes can predict stroke outcome.
Prof. Dr. med. Peter Kühnen, MSc
Charité – Universitätsmedizin Berlin, Institute of Experimental Pediatric
Email: peter.kuehnen@charite.de
Fields of Research
- Epigenetic Regulation of Body Weight
- Pharmacological Treatment of Rare Forms of Obesity
Project Title
Epigenetic Regulation of Body Weight and Thyroid Function
Project Description
Epigenetic modifications are playing an important role in the regulation of different processes. It has been described initially in rodent studies that DNA methylation differences of so-called metastable epialleles can lead to obesity (Morgan et al. 1999) or phenotype variability (Rakyan et al. 2003). For this reason, we have analyzed DNA methylation in obese individuals and in monozygotic discordant twins with congenital hypothyroidism. Inter- generational and environmental effects have been investigated in different cohorts and tissue samples. Apart from epigenetic mechanisms, obesity could occur in rare cases due to monogenic defects. As a conservative treatment (increased exercise, reduced caloric intake) and bariatric surgery is not successful in these patients to reduce hyperphagia and stabilize body weight, we have started an investigator-initiated phase 2 trial, in which patients with deficiencies of the leptin-melanocortin pathway, a cascade which is pivotal for the regulation of satiety, are treated with an MC4R agonist.
PD Dr. med. Annette Künkele
Charité – Universitätsmedizin Berlin, Department of Pediatrics, Division of Oncology and Hematology
Email: annette.kuenkele@charite.de
Fields of Research
- Immunotherapies
- CAR‐T‐cell Therapy
- Neuroblastoma
Project Title
A CAR-T-Cell Approach for Solid Tumor Attack Using Neuroblastoma as a Model
Project Description
Targeting tumors by adoptive T-cell therapy is a promising innovative approach that hijacks the immune system to direct effector mechanisms against metastatic and resistant tumor cells. One form uses chimeric antigen receptors (CARs) to target tumor-associated antigens, which while successful against leukemia and lymphomas has not yet made strides against solid tumors. I am interested in optimizing CAR-T-cell therapy for solid tumors to remove the current difficulties that the solid tumor environment presents for this innovative harnessing of immune potential against cancer cells. During my post- doc time in Seattle, I developed a CAR specific for CD171, an antigen expressed in several solid tumors including neuroblastoma, the most common extracranial tumor in childhood with an overall survival of less than 50% in high-risk patients. My current research interest is to increase the persistence and efficacy of CAR-T-cell-based immunotherapy for children with neuroblastoma using
the CD171-CAR. I will focus on a) a 3D neuroblastoma cell culture model to investigate which CAR constructs enable T-cells to invade solid tumors, b) structurally CAR construct optimization to regulate activation and target binding, and c) an analysis of the influence of oncogenic MYCN activity on the tumor microenvironment and CAR- T-cell effector function, which also tests the efficacy of combining drugs targeting MYCN with CAR-T-cell therapy. In order to dissect the mechanisms leading to either tumor eradication or relapse, I will use a syngeneic mouse model for the transferred T-cells and the host. The CD171-CAR will be introduced into CD8+ T-cells derived from a mouse expressing a single TCR with tumor unrelated specificity (OT1/Rag-/-). This way T-cell-derived species-specific cytokines such as interferon gamma can only act on the tumor stroma and cancer cell recognition by T-cells occur exclusively through the CD171-CAR.Prof. Dr. med. Annette Künkele
Charité – Universitätsmedizin Berlin, Department of Pediatric Oncology and Hematology
Email: annette.kuenkele@charite.de
Fields of Research
- Pediatric stem cell transplantation
- Cellular immunotherapies
Project Title
Development, Production and Application of CAR-T Cell Therapy for Children with Solid Tumors
Project Description
My main clinical interest is in pediatric hematopoietic stem cell transplantation (HSCT), where I am an attending physician. This form of immunotherapy was started with the idea that a »new« allogeneic immune system would help fight cancer. An innovative, very promising form of immunotherapy is chimeric antigen receptor (CAR)-T cell therapy, in which patients’ immune cells are genetically modified to be able to specifically recognize and destroy tumor cells. I am responsible for the selection, treatment and follow-up of these patients as the principal investigator
of all CAR-T cell studies at our center. While great success has already been achieved with CAR-T cell therapy in leukemias and lymphomas, success in the treatment of solid tumors is still lacking.
My scientific focus is therefore on the development and optimization of CAR-T cell therapy for solid tumors. In this regard, my research group focuses on (i) the discovery of novel tumor-specific targets for CAR-T cells, (ii) the enhancement of tumor infiltration ability and improved function/persistence of CAR-T cells in tumors, and (iii) smart therapy combinations that combat resistance mechanisms. As a Clinician Scientist, my top priority is to bring CAR-T cell therapies to patients. Therefore, an important cornerstone in linking my research concept to my clinical focus is to establish a GMP-compliant
manufacturing platform for CAR-T cells on site and to build an infrastructure that ensures the safe delivery of these novel cell therapies to patients.PD Dr. med. Florian Kurth, MSc
Charité – Universitätsmedizin Berlin, Medical Department, Division of Infectiology and Pneumonology
Email: florian.kurth@charite.de
Fields of Research
- Infectious Diseases
- Parasitology
- Malariology
Project Title
Delayed Haemolysis Following Artemisinin Therapy of Malaria
Project Description
Malaria remains the most important vector-borne infectious disease in humans. Its importance has been recognized also recently by the award of the 2015 Nobel Prize in medicine to the malariologist Tu Youyou. Artemisinins have become the most important class of antimalarials during the last decade. They are superior to all other antimalarials in terms of efficacy, safety, and tolerability. Episodes of severely delayed hemolysis have recently been observed in non-immune patients treated with Artemisinins for severe malaria. More than 80% of these patients required red blood cell transfusion and re-hospitalization. Post-Artemisinin delayed hemolysis (PADH) has also been reported in a cohort of African children with severe malaria. The pathophysiological background, exact incidence and risk factors of PADH are still poorly understood. The research program aims at addressing these open questions within the following sub-projects: The epidemiology and clinical presentation of PADH will be assessed in a clinical study in cooperation with the European network for tropical medicine and travel health (Tropnet). Thereby the incidence and possible risk factors of PADH will be identified. Primary human hepatocytes will be used to metabolize artemisinins in an In-vitro model. Metabolites with the potential to induce auto-immune mediated hemolysis will thereby be identified. Simultaneous analysis of the cytochrome-profile of the employed hepatocytes will allow assessing inter-individual differences in the pharmacokinetic properties of Artemisinins with respect to different cytochrome-isoenzymes. Changes in membrane properties of red blood cells after malaria will be analyzed using flow cytometry. Results will be used to decipher the underlying mechanism of erythrocyte loss in PADH. Results of this integrative multipronged research project shall help to improve the drug safety of Artemisinins as the most important class of antimalarials.
PD Dr. med. Gunnar Lachmann
Charité – Universitätsmedizin Berlin, Department of Anesthesiology and Operative Intensive Care Medicine
Email: gunnar.lachmann@charite.de
Fields of Research
- Immune Function in Critically ill Patients
- Immune Stimulation in Immune Suppression
- Hemophagocytic Lymphohistiocytosis in ICU
Project Title
Biomarkers for Adult Hemophagocytic Lymphohistiocytosis in Critically ill Patients
Project Description
Hemophagocytic Lymphohistiocytosis (HLH) is a rare life-threatening hyperinflammatory syndrome with a mortality rate of 68%. It often remains undiagnosed due to sepsis-like symptoms. Early and reliable diagnosis of HLH in the intensive care unit (ICU) is pivotal for patient outcome. It is known that adult HLH is triggered mainly by infectious diseases, malignancies, immune deficiency and autoimmune diseases, leading to an impaired function of cytotoxic T lymphocytes and natural killer cells. This results in an excessive immune activation of macrophages and T-cells with extreme cytokine production of interferon γ (IFN-γ), and tumor necrosis factor α (TNF-α) – the so-called cytokine storm. These highly activated macrophages and the »cytokine storm« infiltrate lymphoid and non-lymphatic tissues and lead to hemophagocytosis and multiple organ failures. Within this project, we plan to build up a biobank and systematically investigate this life-threatening hyperinflammatory syndrome in the ICU in order to detect biomarkers for an early diagnosis. The project aims to find a highly sensitive and highly specific biomarker panel to significantly improve the currently available diagnostic possibilities, to get further insights into its pathophysiology, and subsequently to reduce mortality. In particular and driven by previous studies, we analyze CRP, PCT, IL-1β, IL-6, IL-8, IL-10, TNF-α, IFN-γ, SIL-2R, ferritin, ferritin, EBV and CMV viral load, the microRNAs miR-205-5p, miR- 194-5p and miR-30c-5p, perforin and CD107a.
Dr. med. Michael Launspach
Charité – Universitätsmedizin Berlin, Department of Pediatric Oncology and Hematology
Email: michael.launspach@charite.de
Fields of Research
- Pediatric Oncology
- Regenerative Therapies
- Gene Therapy
- Cell engeneering
- CRISPR/Cas
Project Title
Neuroblastoma Tumor Microenvironment Alteration Through a Gene Therapeutic Approach to Enhance Adoptive T Cell Therapy
Project Description
The gene therapeutic approach we are developing aims to modify neuroblastoma cells by CRISPR/Cas9 technology to express transgenes that encode for a T cell-attracting chemokine: CXCL10. By doing so, we aim improve CAR T cell infiltration and subsequently efficacy, even in tumors with a T cell excluding signature. To achieve transgene expression predominantly in cancer cells we will be using the sequence specificity of the CRISPR/Cas9 system. We thereby compare different genomic targets in terms of integration frequency, transgene expression and tumor specificity.
Dr. med. Anne Lesemann
PD Dr. med. Thomas Liman, MSc
Dr. med. Agustin Liotta
Charité – Universitätsmedizin Berlin, Department of Anesthesiology and Operative Intensive Care Medicine
Email: agustin.liotta@charite.de
Fields of Research
- Anesthetics
- Neurophysiology
- Neurometabolism
Project Title
Impact of Anesthetics on Cerebral Energy Metabolism During Light and Deep Anesthesia: Possible Implications for Postoperative Neurological Complications
Project Description
Anesthesia is a state of pharmacologically induced unconsciousness, amnesia, and analgesia that allows surgery and intensive care treatment – undoubtedly a key element of modern medicine. However, deep anesthesia is associated with postoperative delirium and lasting cognitive decline. The underlying mechanisms of these post- operative complications are largely unknown. The depth of anesthesia can be classified by typical EEG patterns. Burst suppression (BS) and isoelectricity characterize deep anesthesia and correlate with hypometabolism in the brain. Similar EEG-patterns also occur during situations with energy mismatch such as hypoxia or traumatic brain injury, suggesting similar but reversible effects of anesthetics on cerebral metabolism. In the clinical routine, the use of deep anesthesia to reduce metabolism and evoke neuroprotection is controversial as anesthetics impair mitochondrial function. Importantly, the relationship between mitochondrial dysfunction and depth of anesthesia was not yet systematically studied. In my work, my colleagues and I aim to characterize the effects of anesthetics on the oxidative phosphorylation and function of neurons during different anesthetic regimes in vitro (i.e. brain slices) and in vivo in rats. Combining oxygen-measurements, electrophysiology and flavin adenine dinucleotide (FAD)-imaging with computational modeling, we want to predict possible targets of anesthetics in the mitochondrial enzymatic system. Understanding mitochondrial function during deep anesthesia will increase our knowledge on the pathophysiology of post- operative neurological complications. Furthermore, comparing gaseous and intravenous anesthetics has clinical relevance for appropriate therapeutic choice. Last, the use of multiparametric measurements and computational modeling could lead to find new biomarkers and improve monitoring during surgery and clinical situations in which deep anesthesia is performed such as status epilepticus or high intracranial pressure.
Dr. med. Roxanne Lofredi
Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology
Dr. med. Jana Lücht
Charité – Universitätsmedizin Berlin, Department of Pediatric Cardiology and Congenital Heart Disease
Email: jluecht@dhzb.de
Fields of Research
- Translational Medicine
- Pediatric Cardiology
- Inflammation
Project Title
Cold Inducible RNA-Binding Protein (CIRBP) as a Diagnostic Marker in Pediatric Cardiac Surgery
Project Description
Both inflammatory reactions and capillary leak syndrome are frequent complications after open-heart surgeries in children with congenital heart disease. Capillary leak syndrome is primarily induced by endothelial dysfunction and is characterized by intravasal volume- and protein depletion, as well as edema. Inflammatory reactions and capillary leak syndrome crucially influence postoperative morbidity as they are associated with a longer stay on the pediatric intensive care unit, prolonged mechanical ventilation and higher demands for catecholamines and sedative medication. To date, only a few risk factors have been identified for the development of inflammatory reactions and capillary leak syndrome. However, we are still lacking suitable biomarkers, which can be used to detect and treat patients at risk early on. Cold inducible RNA binding protein (CIRBP) belongs to the family of coldshock proteins and has been identified as a potent inflammatory mediator. So far, basic research and clinical studies indicate that CIRBP may be of both diagnostic and therapeutic use for inflammatory reactions. Furthermore, experimental studies have shown that CIRBP is involved in the pathogenesis of endothelial dysfunction. As there have been no studies analyzing CIRBP concentrations in peripheral blood after cardiac surgery in children with congenital heart disease, the present pilot study is designed to evaluate CIRBP as a potential diagnostic marker in this cohort. Therefore, patients up to the age of 18 years undergoing a corrective or palliative cardiac surgery at our center will be recruited for the study. Blood samples will be collected directly before and during the first 24 hours after operation at defined time points. In addition to analyzing CIRBP, proinflammatory cytokines, and markers for endothelial dysfunction, serum samples will be incubated with human monocytes (THP-1) and endothelial cells (HUVECs) in the experimental part of the study to analyze induced mechanisms on a cellular level.
PD Dr. med. Alawi Lütz
Julia Macos
Charité-Universitätsmedizin Berlin, Klinik für Pädiatrie m.S. Onkologie und Hämatologie (CVK)
Email: julia.macos@charite.de
Fields of Research
- pediatric oncology
- solid tumor microenvironment
- CAR T cell therapy
Project Title
Evaluating the effect of intra-tumoral cytokine secretion after tumor microenvironment gene therapy on CAR T cell therapy
Project Description
Therapy-resistant solid tumors represent a growing global challenge. Neuroblastomas are examples of solid tumors and as the most common extracranial solid tumor of childhood responsible for 15% of childhood cancer-related deaths. The overall survival for high-risk cases is still not exceeding 50% and treatment options are limited in cases of relapse. One novel approach could be adoptive T cell therapy with chimeric antigen receptor (CAR) T cells. Response rates in CAR T cell treatment of solid tumors are not yet sufficient due to a series of hurdles, especially insufficient T cell infiltration and an immunosuppressive tumor microenvironment as present in neuroblastoma. While much effort is being put into engineering T cells, striving to tackle the aforementioned limitations and improve response rates this study wants to develop a gene therapeutic approach that alters the tumor microenvironment in a way that T cell and CAR T cell infiltration is increased, and immunosuppression is reduced.
The aim of the group is to develop a CRISPR/Cas targeted cytokine gene therapy to overcome the hurdles of an immunosuppressive tumor microenvironment and to facilitate CAR T cell therapy in solid tumors. The approach aims to modify neuroblastoma cells by CRISPR/Cas9 technology to express transgenes that encode for T cell-attracting chemokines or T cell-stimulating cytokines. Their secretion within the tumor will improve CAR T cell infiltration and efficacy. After in vitro proof of concept for the targeted CRISPR transgene knock-in has been obtained in neuroblastoma cell lines the project will now focus on the evaluation of the effector arm of the proposed gene therapeutic approach that is the multi-modal evaluation of the cytokine effects on neuroblastoma directed CAR T cell therapy in vitro and in vivo.PD Dr. med. Anna-Karina Maier-Wenzel
Charité – Universitätsmedizin Berlin, Department of Ophthalmology
Email: anna‐karina.maier@charite.de
Fields of Research
- Posterior Lamellar Keratoplasty
- Intraocular Pressure Elevation
- Corneal Angiogenesis and Lymphangionesis
Project Title
Evaluation of Surgical Technique of Posterior Lamellar Keratoplasty and Postoperative Complications
Project Description
Corneal endothelial disorders like Fuchs endothelial dystrophy and bullous keratopathy were treated by penetrating keratoplasty (PKP) since years. Prolonged visual rehabilitation of over a year, high astigmatism, suture-related complications and graft rejection are common complications after PKP. Alternative surgical techniques like Descemet Stripping endothelial keratoplasty (DSEK) or Descemet membrane endothelial keratoplasty (DMEK) have been developed over the last decade and allow the transplantation of posterior corneal layers instead of the complete cornea. Whereas in the DSAEK procedure the technique with graft preparation and graft unfolding is well standardized and reproducible, the technique of DMEK surgery remains challenging. Especially, the main step of the surgical technique of DMEK, the unfolding of the lamella to attach the graft to the posterior stroma, poses difficulties. During this step, the most manipulations to the graft occur. We investigated if the more difficult unfolding correlates to donor characteristics and to the final outcomes (Maier et al., Graefes, 2015). Additionally, we evaluated, if the localization of the surgical approach influences the postoperative outcomes (Maier et al., Am J Ophthalmol, 2015). Postoperative complications like graft detachment, graft rejection, and postoperative intraocular pressure elevation occur also after DMEK. We analyzed the rate and localization of graft detachment (Maier et al., Cornea, 2016). Addition- ally, we investigated the incidence of postoperative intraocular pressure elevation and analyzed causes and risk factors (Maier et al., Graefes, 2014, Maier et al., J of Glaucoma, 2017). Corneal angiogenesis and lymphangiogenesis are associated with a higher risk of graft rejection after corneal transplantation. We study the role of different factors like ECM molecules in the development of these blood and lymphatic vessels (Maier et al., IOVS, 2017).
Smilla Maierhof
Charité-Universitätsmedizin Berlin, Klinik für Neurologie mit experimenteller Neurologie (CCM)
Email: smilla.maierhof@charite.de
Fields of Research
- Peripheral Nervous System
- Neurotoxicity
- Translational Stem Cell Research
Project Title
Modeling Chemotherapy-induced polyneuropathies in iPSC-derived sensory neurons
Project Description
In my MD-PhD project, I aim to elucidate the molecular mechanisms of chemotherapyinduced polyneuropathy (CIPN) in a human iPSC-based sensory neuron model while outlining novel potential treatment strategies. Conducting a multi-omic approach including RNA sequencing, deep proteome and lipidome analyses, I aim to explore signaling cascades involved in acute and chronic CIPN. Identified neurodegenerative pathways, e.g., leading to mitochondrial damage, caspase activation and alterations in TRP channel expression, are validated in cellular assays as well as in multielectrode arrays.
In the second part of project, a CRISPR-Cas9 iPSC-knockout cell line for the neuronal calcium sensor protein 1 (NCS1) was created and iPSC-derived sensory neurons (iPSC-DSN) differentiated. The potentially lowered susceptibility of this genetically modified iPSC-DSN vs. wildtype cell line was investigated with different molecular as well as electrophysiological methods. By using patient-specific iPSCderived sensory neurons (iPSC-DSN), we strive to correlate the experimental data to the clinical phenotype to lay a foundation for exploring interindividual differences in susceptibility and disease progression in peripheral neurotoxicity-mediated neuropathies.Dr. med. Tazio Maleitzke
Charité – Universitätsmedizin Berlin, Center for Musculoskeletal Surgery
Email: tazio.maleitzke@charite.de
Fields of Research
- Osteoarthritis
- Cell-based Therapies
- Mesenchymal Stromal Cells
- Bone
Project Title
Disease Modifying Osteoarthritis Cell Therapy
Project Description
Osteoarthritis (OA) is the most common form of arthritis worldwide. Chronic low-grade inflammation in the articular environment causes cartilage degeneration at an early disease stage, resulting in chronic pain, disability and loss of independence due to progressive joint destruction. To date, no treatment is available to sustainably combat low-grade inflammation in early-stage OA patients.
PLX-PAD cells, which are adherent mesenchymal stromal-like cells derived from donated human placentas and developed as a cell therapy, demonstrate significant regenerative, immunomodulatory, and anti-oxidative properties. Specifically, through the regulation of SDF-1, IL-1β, and IL-6, PLX-PAD cells have been shown to reduce oxidative stress and the release of pro-inflammatory cytokines while increasing anti-inflammatory IL-11 and CCL5 secretion when challenged by pro-inflammatory signals present in OA. We thus hypothesize that PLX-PAD cells could restore the pathologically altered joint environment, dominated by pro-inflammatory and catabolic signalling cascades.For this project, we follow a combined in vitro and in vivo approach:
1.) Ex vivo / in vitro work will be performed using tibial cartilage samples excised in regular knee arthroplasty surgeries for OA. Obtained OA chondrocyte cultures as well as ex vivo organ culture samples are treated with PLX-PAD, and RT-qPCR, immunohistochemistry, ELISA, and spectrophotometry/DMMB will be conducted to assess cellular and molecular response.
2.) In vivo, we will use the Dunkin Hartley guinea pig model of naturally occurring OA, which is widely established due to a close resemblance to human OA, and which has been used to successfully explore intraarticular therapies for OA. Six-month-old animals will be treated with intraarticular injections of PLX-PAD versus placebo, and compared to healthy controls. Animals receive in vivo MRI scans to detect short- (one month) and long-term (six months) effects of PLX-PAD therapy on cartilage integrity.
Six months following treatment, animals will be euthanized, and among others, histology, immunohistochemistry, and RT-qPCR of knee joints, micro-CT structural analysis of subchondral bone, and serum OA biomarker analysis will be conducted.
Restoring physiological joint homeostasis at an early disease stage may be the key to understanding health to disease progression in OA. Targeting this ‘window of opportunity’ may fundamentally change the way OA is treated today and in the future.Dr. med. Tazio Maleitzke
Charité – Universitätsmedizin Berlin, Center for Musculoskeletal Surgery
Email: tazio.maleitzke@charite.de
Fields of Research
- Osteoimmunology
- Experimental Arthritis
- Calca‐Peptides in Bone Metabolism
Project Title
The Role of Calca-Derived Peptides in Rheumatoid Arthritis
Project Description
Rheumatoid arthritis (RA) affects approximately 1% of today’s world population and is characterized by chronic inflammation of the synovia and concomitant joint destruction, led by cartilage degradation and bone erosions. Bone erosions, originating from an imbalance of bone formation and bone resorption can unfortunately only be partially halted by current anti-rheumatic drugs and often endoprosthetic joint replacements are the patient’s only definitive therapeutic option. Cartilage deg- radation and bone erosions cause severe joint deformities and an overall compromised bone constitution. Poor bone quality makes endoprosthetic surgery more difficult with higher complication rates and poorer outcomes in patients with RA. Calcitonin (CT), procalcitonin (PCT) and calcitonin gene-related peptide (CGRP) are peptides of the bone metabolism that have a lasting impact on the balance of bone formation and bone resorption. Although these peptides are all coded by their common gene Calca their effect on bone tissues is quite diverse. Pharmacological CT acts protective of bone tissue, whereas endogenous CT works as an inhibitor of bone formation. PCT inhibits the differentiation of osteoclasts and CGRP, on the other hand, has an osteoanabolic effect on bone. Despite this knowledge, Calca-derived peptides are, especially in regards to their effect on bone erosions, not well understood. Through a series of experiments with knockout mice for CT, PCT and CGRP-signaling we want to investigate the effect of Calca-derived peptides on experimental autoantibody-mediated arthritis. With the help of radiological, histological and molecular analysis we hope to gather sustainable and applicable results in order to set a new foundation for long-lasting therapeutic strategies, that patients suffering from RA and orthopedic surgeons alike would largely benefit from.
Dr. med. Lukas Maurer
Charité – Universitätsmedizin Berlin, Department of Endocrinology and Metabolic Diseases
Email: lukas.maurer@charite.de
Fields of Research
- Invasive Neuromodulation
- Metabolic Phenotyping
- Electrophysiology
Project Title
Probing and Manipulating Neuronal Circuits in Obesity
Project Description
The prevalence of obesity and type 2 diabetes (T2DM) has reached epidemic proportions worldwide. Primarily reward-related overconsumption of highly palatable, energy-dense foods beyond homeostatic needs is considered a central aspect in the multifactorial pathogenesis of obesity and the accompanying metabolic distortions. Recent cumulative evidence indicates that dysfunctional information flow cortico-striatal networks involved in metabolic regulation, as well as reward processing, may be of primary importance for the pathophysiology of obesity. Progress in the exploration of functional anatomy in a number of neuropsychiatric disorders revealed dysfunctional neuronal processing within cortico-striatal circuits. This aspect and the emergence of deep brain stimulation as a suitable approach to probe and manipulated neuronal activity prompted the concept of circuit disorders for diseases as for example Parkinson’s disease, obsessive-compulsive disorder, addiction, and depression. Due to multiple similarities of the neuronal information processing with respect to obesity and recent advances in dissecting the neurocircuitry involved in the regulation of food intake and metabolism by optogenetic studies, cumulating evidence suggests that obesity might be understood in a similar way as the circuit disorder involving malfunctioning of the cortico-striato-hypothalamic system. We, therefore, aim in our experimental design to investigate local field potential oscillations within this system characterize information processing and to apply deep brain stimulation (DBS) in order to manipulate neuronal activity as a potential therapeutic approach in obesity.
PD Dr. med. Philipp Mergenthaler
Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology
Email: philipp.mergenthaler@charite.de
Fields of Research
- Clinical Neuroscience
- Energy Metabolism
- Regulation of Neuronal Cell Death
Project Title
Targeting Intravital Protein Interactions in Neuronal Energy Metabolism of Stroke
Project Description
This project addresses the pressing need to develop novel treatment approaches for acute neurodegeneration such as it occurs in stroke. Thus, by investigating the pathophysiological basis for acute neurodegeneration on a molecular level, this project will mitigate the future challenges imposed by the care for patients suffering from these diseases. The high energy demand of the brain predisposes it to a variety of diseases if energy supplies are interrupted, such as in stroke. Neurons are particularly intolerant of inadequate energy supply and die or degenerate in either an acutely or chronically disturbed metabolic environment. Therefore, the goal of this project is to unravel the role of the tight connection between glucose metabolism and the regulation of cell death pathways for neuronal viability or acute neuronal degeneration after ischemic injury. I have previously characterized a multiprotein complex centered around the mitochondrial glycolytic enzyme hexokinase II (HKII), which acts as a sensor of the metabolic state of neurons (Mergenthaler et al., Proc Natl Acad Sci USA 2012) and provides a prototypic mechanistic example of the interdependence of these major cellular pathways (Mergenthaler et al., Trends Neurosci 2013). The main hypothesis of this project is that regulation of the interaction of HKII and its associated multiprotein complex links metabolism to programmed cell death in neurons. Protein:protein interactions can be highly dependent on the physiological context and may be regulated differently in different T-cells. Therefore, in addition to verifying the HKII protein interactions in living cells, I am using live human induced pluripotent stem cell (hiPSC)-derived neurons and human brain organoids to express HKII and its putative interactors with fluorescent protein tags at near-endogenous levels. In vitro differentiation of hiPSCs will permit examining these interactions in human neurons.
Dr. med. Robert Mertens
Charité – Universitätsmedizin Berlin Department of Neurosurgery (including Pediatric Neurosurgery)
Email: robert.mertens@charite.de
Fields of Research
- Moyamoya Disease
- Cerebrovascular Diseases
- Vascular Neurosurgery
Project Title
Development and Characterization of a Human Chip-Based Organoid Model of Moyamoya Disease
Project Description
The Moyamoya Disease (MMD) is a cerebrovascular disease characterized by progressive spontaneous bilateral occlusion of the terminal internal carotid arteries (ICA) and their major branches with compensatory capillary collaterals resembling a »puff of smoke« (Japanese: Moyamoya) on cerebral angiography. Symptoms are attributed to reduction of the blood flow resulting from stenosis of the ICA (ischemia) and the fragility of the compensatory collaterals (hemorrhage) which frequently leads to severe disability or death. Due to the early age of onset,
familial cases and the occurrence predominantly in the East Asian population, genetic causes were suggested. Recently, a variant of the RNF213 gene was shown to be strongly associated with MMD in the East Asian population, but lacks full penetrance. The multifactorial pathophysiology of MMD still remains to be understood. No diagnostic or prognostic biomarkers have been validated yet and no causal therapy to limit the stenotic lesions or the development of the fragile collateral network is
available. The lack of knowledge about the pathophysiology and the lack of biomarkers and causal therapy constitute an unmet research and medical need for this severely affected group of patients. Furthermore, no validated animal or in vitro disease model exists for MMD. In compliance with the 3R principles, the primary aim of this project is to develop and characterize a human in vitro MMD model with perfusable vessel-networks on organoid chips for the first time, which could also be
adapted to various other vascular diseases. Importantly, the different contribution of blood vessel cells such as endothelial (EC) and mural cells is debated but essential for elucidating the specific pathophysiology of MMD and current animal models of the disease cannot distinguish the influence of different cell types on the phenotype. By using genetically modified, RNF213 mutated human
ECs and mural cells as well as patient-derived human induced pluripotent stem cells (hiPSCs) to develop complex, MMD-specific 3D vessels on a chip we aim to investigate the pathophysiology based on the specific role and dynamic interactions of selected cell types, thereby reducing and replacing animal models. In parallel, we are preparing and sampling for a multi-omic analysis of
our European MMD cohort. In a future translational, multi-disciplinary approach, we aim to translate findings of the multi-omic analysis into our organoid model.Prof. Dr. med. Alexander Meyer
Charité – Universitätsmedizin Berlin, German Heart Center Berlin, Department of Cardiothoracic and Vascular Surgery
Email: meyera@dhzb.de
Fields of Research
- Machine Learning
- Data Science in Medicine
- Medical Computer Science
Project Title
Big Data Analytics in Health Care – Medical Data Science to Improve Patient Safety During Intensive Care
Project Description
Machine learning applications have become ubiquitously popular – from smart mobile phone applications via smart homes to entire smart industries. This family of data-driven methods thrives especially in settings where a large number of concurrent signals go well beyond the capacity of human reasoning. Critical care units are a highly challenging environment that confronts physicians with a demanding caseload and requires rapid decision-making. The handling of a continuous stream of massive amounts of noisy data, such as laboratory results, clinical and physiological measurements as well as imaging and increasingly »omics« information can easily go beyond the information processing capacity of the human operator (intensive care physician) and may lead to treatment delays or clinical errors. Our work applies deep machine learning methods in a critical care scenario to provide timely and highly accurate decision support to clinical staff. We aim to push the translation into the clinical routine by performing rigorous clinical validation.
Dr. med. Jochen Michely
Charité – Universitätsmedizin Berlin, Department of Psychiatry and Neurosciences
Email: jochen.michely@charite.de
Fields of Research
- Computational Psychiatry
- Cognitive Neuroscience
- Psychopharmacology
- Neuroimaging
Project Title
Towards a Computational Account of Ketamine’s Antidepressant Effect
Project Description
With an estimated 350 million people affected globally, depression represents one of society’s most challenging and costly health burdens. Traditional pharmacotherapy of depression increases brain levels of monoaminergic neurotransmitters, such as serotonin. However, effects of monoaminergic antidepressants are often modest, and benefits emerge slowly, over a time course of weeks. Recently, an NMDA receptor antagonist, ketamine, was found to improve mood in severe, treatment-resistant depression. Unlike traditional therapy, ketamine acts rapidly, producing antidepressant effects within hours of application. Moreover, ketamine targets glutamate neurotransmission, rather than impacting brain monoamine levels. Consequently, the serendipitous discovery of this novel, rapid-acting antidepressant is hailed as one of the most important advances of modern psychiatry. However, despite ketamine’s promising clinical impact, the mechanisms through which it may work remain elusive. To utilise the enormous therapeutic potential of ketamine, we require a better mechanistic, neuroscientifically grounded, understanding of its effect
on brain function. In this project, I will use cognitive assessment, brain scanning and mathematical modelling, in patients undergoing ketamine treatment. Over the course of the study, patients will be repeatedly tasked on a bespoke decision-making task that I have recently validated in a similar pharmacological study (Michely et al., 2020, Nat Commun). This gamified computer task enables a precise assessment of how patients learn from, and emotionally respond to, rewarding experience. Additionally, I will use non-invasive, functional magnetic resonance imaging (fMRI), allowing me to probe activation of brain circuits involved in human reward processing. Building on a computational psychiatry approach, I aim to decipher the cognitive mechanisms that give rise to ketamine’s antidepressant effect, and identify neurocomputational markers for a clinical response to intervention. Informed by a deeper understanding of the neurobiology of depression and its treatment, my goal is to improve tailoring of currently available, and development of novel antidepressant therapies in the future.Dr. med. Simon Moosburner
Charité – Universitätsmedizin Berlin, Department of Surgery
Email: simon.moosburner@charite.de
Fields of Research
- Liver Transplantation
- Extended Criteria Donor Organs
- Proteomics
Project Title
Extracorporeal Evaluation of Liver Grafts from Older Donors
Project Description
Liver transplantation is the treatment of choice for patients with advanced liver cirrhosis, hepatocellular carcinoma within Milan-criteria, and severe metabolic or autoimmune hepatic disorders. However, the number of patients waiting for liver transplantation exceeds the number of available organs. Notably, in Germany, the success of liver transplantation has been limited by a dramatic decline in organ donation over the last decade. To alleviate the supply and demand imbalance, an increasing proportion of grafts meeting so called extended donor criteria (i.e. high donor age or macrovesicular steatosis hepatis) are accepted for transplantation. These extended criteria donor organs are usually discarded due to a higher susceptibility for ischemia reperfusion injury (IRI), which associated with an increased rate of primary non-function and early allograft
dysfunction. IRI is initiated during warm reperfusion of livers in situ after static cold storage, which remains the current standard of care. A recent alternative to static cold storage is normothermic ex vivo liver machine perfusion (NEVLP): livers are perfused with an oxygenated medium to achieve an almost physiological milieu prior to transplantation. NEVLP enables 1) reduced IR, 2) organ evaluation and characterization prior to transplantation, 3) optimized transplantation logistics, 4) potential for metabolic conditioning during perfusion. Ex vivo machine perfusion therefore has the potential to increase the pool of available organs for transplantation. Currently, around 15% of potential liver grafts are declined in Germany due to donor age or morbidity. Indeed, this problem exists worldwide with similarly high decline rates in the United States with 13%. However, it still remains unclear why some organs from older age donors perform better after transplantation than others. The aim of the project EvALT (Extracorporeal Evaluation of Liver Grafts from older Donors) is therefore to characterize older donor organs during NEVLP using a previously developed small animal model for NEVLP and possibly identifying therapeutic targets for future graft optimization prior to transplantation.Dr. med. Agata Mossakowski
Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology
Email: mossakowski.agata@gmail.com
Fields of Research
- Intravital Microscopy and Fluorescence Lifetime Microscopy
- Neuromuscular Diseases
Project Title
Oxidative Stress in Muscle Diseases
Project Description
Oxidative stress is a major factor in the progression of muscle diseases, proving to affect cellular signaling pathways, enzyme expression, membrane stability and cellular regeneration. Conclusions about the origin of oxidative stress are currently drawn indirectly on the presence of free radicals, their oxidation products and expression subunits of the enzymes involved. With the establishment of NAD(P)H-fluorescence lifetime microscopy in chronic neuroinflammation we were able to for the first time monitor the genesis of oxidative stress intravitally, in real time and without influencing the system through staining or fixation by measuring the activity of NADPH-oxidase, the main source of reactive oxygen species (Mossakowski et al, Acta Neuropathologica 2015). Instituting NAD(P)H-fluorescence lifetime microscopy in muscle tissue will complement the hitherto existing means of diagnostics and pathophysiological research in neuromuscular disease, adding a new metabolic monitoring system that, in the long run, might be used to diagnose oxidative shifts in muscle tissue even before the appearance of histopathological changes. The method can potentially be used to monitor disease-modifying therapies by directly detecting the dynamics and impact of antioxidants on the ROS production in muscle tissue. The aim of this work is thus to establish NAD(P)H-fluorescence lifetime microscopy, previously used in other tissues and cell types, in muscle tissue and to ensure a valid transfer between intravital and ex vivo measurements. We use a custom-built multiphoton laser microscope with a time-correlated single photon counter as part of the intravital microscopy network JIMI (German Rheumatism Research Center, Max Delbrück Center and Hans Knoell Institute) and cooperate with Dr. rer. nat. Raluca Niesner, group leader of Biophysical Analytics at the German Rheumatism Research Center.
Dr. med. Thilo Müller
Charité – Universitätsmedizin Berlin, Department of Pediatrics, Division of Oncology and Hematology
Email: thilo.mueller@charite.de
Fields of Research
- Stem Cell Transplantation
- Graft‐Versus‐Host Disease
- Extracellular Vesicles
Project Title
Preclinical Evaluation of Mesenchymal Stromal Cell-Derived Exosomes for GvHD-Therapy
Project Description
Hematopoietic stem cell transplantation (HSCT) is currently the only therapeutic option for a number of malignant and nonmalignant diseases. Graft-versus-host disease (GvHD) is the most common complication, mainly mediated by donor T lymphocytes attacking host cells and causing multiorgan damage especially affecting the skin, liver and intestines. A severe GvHD is associated with 90% patient mortality. Steroids are the standard first-line therapy. Cell-based second-line therapy with MSCs is standard treatment for steroid-refractory GvHD cases since ten years, and administering MSCs stimulates a response and improves 2-year survival in ~50% of these patients. In the last years it was demonstrated that MSCs do not engraft in the patients, what lead tot he speculation that soluble factors secreted by the administered MSCs may be driving patient response. This was supported by a recent case report of one patient with steroid-refractory GvHD that showed substantial improvement after administration of exosome-enriched MSC supernatant. Exosomes are 70-140 nm microvesicles secreted by cells that contain a variety of biomolecules, and are thought to function as intercellular messengers. This project will establish a patient-derived exosome charac- terization pipeline that assesses biomolecular content via RNA sequencing (RNA-Seq) and allows functional in vitro testing via T-cell proliferation assays to qualitatively and quantitatively explore the immunemodulatory potential. Furthermore, exosomes from different donors will be compared, and exosomes from patients will be associated with their clinical course in terms of GvHD occurrence to predict associations with specific exosome contents.
Dr. rer. nat. Melba Muñoz Roldán, MSc
Charité – Universitätsmedizin Berlin, Department of Dermatology, Venerology and Allergology
Email: melba.munoz‐roldan@charite.de
Fields of Research
- Mast Cells in Viral Infections
- Inflammatory Skin Diseases
- Novel Mast Cell and T‐cell Interactions
Project Title
Mechanisms of Mast Cell and T-Cell Interactions Interactions During Viral Infections
Project Description
Mast cells (MCs) are widely considered to be crucial for innate immune responses; however, several groups have recently shown that MCs are also important in the development of protective adaptive immune responses against viruses. Most of these recent studies examined the role of MCs in the recruitment of virus-specific T-cells. In contrast, the role and relevance of MCs in the priming of CD8 T-cells in the context of viral infections is ill characterized and not fully understood. To address this question, we examined the role of MCs in the priming and activation of CD8 T-cells during lymphocytic choriomeningitis virus (LCMV) infection. We found that endogenous CD8 T-cells specific to the dominant LCMV glycoprotein und nucleoprotein epitopes GP33 and NP396 are strongly reduced in MC deficient infected mice as com- pared to wild type controls. In this project, we aim to
dissect the molecular and cellular mechanisms under- lying the effects of MCs on CD8 T-cell priming and activation during viral infections. To this end, we will em- ploy comprehensive in vitro and in vivo analyses to identify and characterize signals that are important for CD8 T-cell priming by MCs in viral infections. A better under- standing of the impact of MCs on CD8 T-cell responses may help to improve antiviral immunity and to modulate and ameliorate inflammatory responses during vi- ral infections of the skin such as herpes viral infections.Dr. rer. nat. Melba Muñoz Roldán, MSc
Charité – Universitätsmedizin Berlin, Department of Dermatology, Venerology and Allergology
Email: melba.munoz‐roldan@charite.de
Fields of Research
- Mast Cells in Viral Infections
- Inflammatory Skin Diseases
- Novel Mast Cell and T‐cell Interactions
Project Title
Mechanisms of Mast Cell and T-Cell Interactions Interactions During Viral Infections
Project Description
Mast cells (MCs) are widely considered to be crucial for innate immune responses; however, several groups have recently shown that MCs are also important in the development of protective adaptive immune responses against viruses. Most of these recent studies examined the role of MCs in the recruitment of virus-specific T-cells. In contrast, the role and relevance of MCs in the priming of CD8 T-cells in the context of viral infections is ill characterized and not fully understood. To address this question, we examined the role of MCs in the priming and activation of CD8 T-cells during lymphocytic choriomeningitis virus (LCMV) infection. We found that endogenous CD8 T-cells specific to the dominant LCMV glycoprotein und nucleoprotein epitopes GP33 and NP396 are strongly reduced in MC deficient infected mice as com- pared to wild type controls. In this project, we aim to
dissect the molecular and cellular mechanisms under- lying the effects of MCs on CD8 T-cell priming and activation during viral infections. To this end, we will em- ploy comprehensive in vitro and in vivo analyses to identify and characterize signals that are important for CD8 T-cell priming by MCs in viral infections. A better under- standing of the impact of MCs on CD8 T-cell responses may help to improve antiviral immunity and to modulate and ameliorate inflammatory responses during vi- ral infections of the skin such as herpes viral infections.Firdevs Murad
Max Delbrück Center, AG Lewin
Email: Firdevs.murad@mdc-berlin.de
Fields of Research
- systems neuroscience
- behavioral neuroscience
- neuroanatomy
Project Title
Identification of neural substrates for processing social vocalizations
Project Description
The naked mole-rat (Heterocephalus glaber, NMR) is an extremely vocal and social rodent, which exhibits several layers of complex sociality such as cooperation, altruism and the use of colony specific vocal dialects. Many of these features are hallmarks of human social behavior and difficult to model in traditional laboratory species. We seek to shed light on the molecular basis underlying the processing of social vocalizations by employing the naked mole-rat as a new model organism.
Our initial aim is to map naked mole-rat brain regions that are active during social and vocal behaviors by using c-Fos expression as a proxy for neural activity. Moreover, we compare the brain activation maps, transcriptome, anatomical gene expression patterns and the vocal repertoire of the NMR and that of closely related species from the African mole-rat family (Bathyergidae). With this comparative approach, we hope to gain a better understanding on how the naked mole-rat brain supports its unique social behavior.Dr. med. Marcel Naik
Charité – Universitätsmedizin Berlin, Department of Nephrology and Medical Intensive Care
Email: marcel.naik@charite.de
Fields of Research
- Nephrology
- Transplantation
- Immunology
- Telemedicine
Project Title
T-Box: A Model for Predicting Kidney Transplantation Failure
Project Description
Marcel Naik started his academic career during his medical school and did his thesis under supervision of Prof. Dr. Klemens Budde investigating immunosuppressive effects in immune cells for individualization of immunosuppressive therapy in renal-transplanted patients. He was introduced into relational databases and statistical analysis. He developed interest in the problems of a clinical routine database with missing values and suboptimal normalization. In his BIH funded project, he pursues to establish a prediction model for clinical use in the nephrology department at Charité to determine patients at high risk for renal transplant failure or death. Despite advances in treatment graft loss occurs in 5% of patients annually, so that 50% are back on dialysis after 10 years. Unfortunately, early detection of patients at high risk is lacking. Patient data from the clinical transplant database »TBase« is retrieved including all patients above 18 years who had undergone only kidney transplantation at Charité, Campus Mitte, after 2000. Data consists of demographic data of recipient, transplant and donor, examination reports from microbiology, pathology and clinical notes, laboratory values and hospitalizations at Charité. All data needs to be refi ned and cleared from missings or corrupt data. After that step of data preprocessing a training dataset will be defi ned to train an algorithm predicting patients with permanent renal graft failure or death. Collaborating with the DATEXIS group at Beuth university for applied science text data from examination and pathology reports will be incorporated into the prediction model. Diogo Telmo Neves, a data scientist from the medical informatics department at Charité and former DFKI researcher, is programming and fusing all branches together. As of 04/2021 a baseline prediction model incorporating demographic data is established using KNN- and Random Forest algorithm. To incorporate the individual patient’s timeline into the prediction model a time dependent long short-term memory network will be set up. Furthermore, data from newly established home monitoring of vital sign will be included for detecting early signals. All models will be validated using another cohort from Charité Virchow Hospital. The prediction model’s risk assessment will be integrated into individual patient record to show the risk to doctors. Ultimately he wants to show the individual risk to the individual patient.
Dr. med. Alexander Heinrich Nave, MSc
Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology
Email: alexander.nave@charite.de
Fields of Research
- Stroke
- Biomarkers
- Metabolism
Project Title
Homeostasis After Stroke – the Effect of Stress-Tests on Metabolic and Cerebral Biomarkers
Project Description
Stroke is a major cause of death and long-term disability worldwide. Despite rehabilitation and optimal secondary prevention, many stroke survivors remain functionally dependent and at a high risk for recurrent vascular events. Impairment of lipometabolism is a risk factor for cardiovascular disease and physical fitness training is thought to promote metabolic and cerebral hemostasis. Because the etiology of stroke is heterogeneous, the use of biomarkers for individual risk prediction is promising, especially when these biomarkers can quantify the ability of the individual to maintain homeostasis. We have initiated the prospective observational Berlin Cream and Sugar study (NCT01378468) to evaluate the metabolic changes after stroke and assess the effect of an oral glucose and triglyceride tolerance test on metabolic homeostasis for individual vascular risk prediction. A second study is the randomized-controlled PHYS-STROKE trial (NCT01953549), where subacute stroke patients receive physical fitness training or relaxation sessions for 4 weeks in addition to usual care. Blood and imaging analyses are performed before and after the intervention to establish new biomarkers for vascular risk prediction and assess potential protective effects of fitness training early after stroke (Nave et al. 2013). In this research project, we hypothesize that A) investigation of hemostatic control of lipometabolism in the acute phase of stroke following a stress test, i.e. oral triglyceride tolerance test (OTTT), will improve the individual risk prediction after stroke. B) Application of anaerobic fitness training after stroke in addition to usual care will lead to a better functional outcome and will improve markers of metabolic homeostasis compared to relaxation sessions. These new markers will include conventional markers of metabolism as well as novel markers, such as different types of microvesicles and expression levels of isolated exosomes. The work will lead to more insight into the role of homeostasis as a key concept in understanding the role of biomarker research.
PD Dr. med. Alexander Heinrich Nave, MSc
Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology
Email: alexander.nave@charite.de
Fields of Research
- Stroke
- Biomarkers
- Metabolism
Project Title
Homeostasis After Stroke – the Effect of Stress-Tests on Metabolic and Cerebral Biomarkers
Project Description
Stroke is a major cause of death and long-term disability worldwide. Despite rehabilitation and optimal secondary prevention, many stroke survivors remain functionally dependent and at a high risk for recurrent vascular events. Impairment of lipometabolism is a risk factor for cardiovascular disease and physical fitness training is thought to promote metabolic and cerebral hemostasis. Because the etiology of stroke is heterogeneous, the use of biomarkers for individual risk prediction is promising, especially when these biomarkers can quantify the ability of the individual to maintain homeostasis. We have initiated the prospective observational Berlin Cream and Sugar study (NCT01378468) to evaluate the metabolic changes after stroke and assess the effect of an oral glucose and triglyceride tolerance test on metabolic homeostasis for individual vascular risk prediction. A second study is the randomized-controlled PHYS-STROKE trial (NCT01953549), where subacute stroke patients receive physical fitness training or relaxation sessions for 4 weeks in addition to usual care. Blood and imaging analyses are performed before and after the intervention to establish new biomarkers for vascular risk prediction and assess potential protective effects of fitness training early after stroke (Nave et al. 2013). In this research project, we hypothesize that A) investigation of hemostatic control of lipometabolism in the acute phase of stroke following a stress test, i.e. oral triglyceride tolerance test (OTTT), will improve the individual risk prediction after stroke. B) Application of anaerobic fitness training after stroke in addition to usual care will lead to a better functional outcome and will improve markers of metabolic homeostasis compared to relaxation sessions. These new markers will include conventional markers of metabolism as well as novel markers, such as different types of microvesicles and expression levels of isolated exosomes. The work will lead to more insight into the role of homeostasis as a key concept in understanding the role of biomarker research.
Dr. med. Mir Timo Zadegh Nazari-Shafti
German Heart Center Berlin, Department of Cardiothoracic and Vascular Surgery
Email: nazari@dhzb.de
Fields of Research
- Temlomere Biology
- Mesenchymal Stem Cells
- Cardiac Regeneration
Project Title
Search for Markers that Can Predict Efficacy of Autologous Stem Cell Therapy in Cardiovascular Disease
Project Description
For regeneration of the damaged heart, autologous MSC transplantation may be a promising alternative or additional treatment option for successfully augmenting the limited regenerative capacity of the adult heart. While preclinical data supported this hypothesis, data from various clinical studies have proven to be less conclusive on the clinical outcomes after autologous MSC- transplantation. Cellular aging and dysfunction in MSCs from donors with severe chronic disease and elderly donors may be responsible for the under-performance of these regenerative cells in certain subjects during the aforementioned clinical trials. Cellular aging and associated cellular dysfunction is caused by multiple factors and may be assessed by the extent of telomere shorten- ing and dysfunction. Investigating and characterizing the telomere biology of MSCs from a larger patient pool with chronic co-morbidities and correlating them to stem cell function in vitro and in vivo as well as to the donor’s medical history may produce more than just one parameter that could predict the clinical outcome of autologous MSC transplantation for cardiovascular regeneration. The aim of this study is to identify predictive markers that would allow estimating the efficacy and success of autologous mesenchymal stem cell therapy for cardiovascular regeneration before administering the stem cells.
Dr. med. Mir Timo Zadegh Nazari-Shafti
German Heart Center Berlin, German Heart Center Berlin at Charité Department of Cardiothoracic and Vascular Surgery
Email: timo.nazari-shafti@dhzc-charite.de
Fields of Research
- Temlomere Biology
- Mesenchymal Stem Cells
- Cardiac Regeneration
- Cardiothroacic Surgery
Project Title
Targeting Inflamed Endothelium with Smart Exosomes for Cardioprotection
Project Description
With the incident of cardiovascular disease on the rise, the natural clinical course in patients after cardiovascular events has become a significant economic burden on our society. In the heart, acute ischemia and reperfusion injury leads to remodeling, and ultimately, to impairment of functionality in affected myocardium. Remodeling is preceded by tissue inflammation, fol-lowed by fibroblast migration and proliferation in the damaged myocardium. Cell based therapies, including neonatal and adult mesenchymal stem cells (MSC), have aimed to prevent myocardial remodeling. In this setting, the cardioprotective effect is in part mediated by extra-cellular vesicles, particularly exosomes. Exosomes contain miRNAs and proteins that can facilitate an antifibrotic, angiogenic and immunemodulatory effect after ischemia reperfusion injury. Despite promising preclinical trials, clinical studies utilizing MSCs in the acute setting of myocardial ischemia failed to demonstrate the reduction of remodeling. It is hypothesized that the positive impact of cell-based therapies on remodeling is inhibited by the low retention rate and survival of MSCs after transplantation. Significant titers of paracrine factors including exosomes are only achieved during the first 24-48 hours after allo-cation of MSCs (»hit-and-run« mechanism) due to limited retention and engraftment of cells. While application of MSCs is usually limited to a one-time injection during cardiac surgery or percutaneous intervention the application of exosomes may allow for repetitive treatments via intravenous applications. The overall objective of this project is to develop a therapeutic exosome product that targets inflamed endothelium in the infarcted myocardium. These smart exosomes (SExs) should exhibit thecapacity to accumulate in the myocardium after ischemia and revascularization upon systemic delivery. Furthermore, they should allow for repetitive application via minimally invasive / percutaneous routes. Finally they should act cardioprotective in situations of myocardial ischemia such as acute infarction.
Dr. med., M. Chem. Christopher Neumann
Charité – Universitätsmedizin Berlin, Department of Hematology, Oncology and Cancer Immunology
Email: christopher.neumann@charite.de
Fields of Research
- Pancreatic cancer
- Organoid cultures
- Personalised therapies
Project Title
Potential of Organoid Cultures to Predict the Therapeutic Response in Patients
Project Description
Pancreatic cancer is a highly malignant tumor with a dismal prognosis. Non-specific symptoms, rapid progress, a high rate of metastasis and very little progress in treatment options result in a five-year survival rate of less than 10% with the only curative treatment to be the surgical resection of the tumor. Pancreatic cancer is expected to be the second deadliest cancer by 2030. Once metastasised the treatment is purely palliative. Only very few chemotherapeutic regimes can be administered. None of them taking into account the specific metastatic patterns patients present. Previous results of the CONKO-01 and -05 study group, however, were able to show a significantly prolonged overall survival of isolated pulmonary metastasis after initial surgical resection compared to isolated hepatic metastasis (30,4 vs. 18,1 months) representing a differential physiology of the tumor. Consequently, possible subgroups of the metastatic stage might benefit from more personalised treatment options. By establishing and analysing patient derived organoid models not only from the primary tumor but also from the different metastatic sides, the tumor physiology as a whole can be understood more thoroughly. The aim of this project is to expose patient derived tumor organoids of the primary and metastatic sides to various targeted and well-known chemotherapies and to use proteomics to classify subgroups and identify potential biomarkers of the tumor. By correlating the in-vitro data to
the clinical response rate of these patients, the organoid model can be evaluated as to whether more personalised therapeutic approaches can become future clinical practice.Dr. med. Marc Joachim Nikolaus
Charité – Universitätsmedizin Berlin, Department of Pediatric Neurology
Email: marc.nikolaus@charite.de
Fields of Research
- Pediatrics
- Autoimmune encephalitis
- Neuroimmunology
Project Title
Mechanisms of Antibody-Mediated Encephalitis in Tumor Disease
Project Description
Encephalitis associated with antibodies against the metabotropic glutamate receptor 5 (mGluR5) is an autoimmune disease characterized by a complex neuropsychiatric syndrome (Ophelia syndrome). It often affects young adults and is associated with Hodgkin lymphoma. mGluR5 belongs to the family of G protein-coupled receptors and activates an intracellular signal cascade. In the past, receptor dysfunction has been associated with schizophrenia, autism, fragile-X syndrome, and Parkinson’s disease. The role of anti-mGluR5 in autoimmune encephalitis though, the underlying pathomechanisms of antibody binding and the link between tumor and autoimmunity remain unclear. Recently, we treated a young patient with Ophelia syndrome and anti-mGluR5 antibodies. We generated monoclonal antibodies of this and other patients’ CSF by using single cell cloning. With tissue- and cell-based assays we characterize the binding patterns and affinities of these anti-mGluR5 antibodies. To address functional effects of the antibody binding we now look for receptor internalization, shifts in cluster localization and impact on cell viability after antibody incubation with neuronal cell cultures. After the encephalitis, the very same patient developed a Hodgkin lymphoma. Immunohistochemistry on biopsy material might now reveal anti-mGluR5 antibody binding. We will compare the results to anti-mGluR5 binding on tumors from non-encephalitic Hodgkin patients as controls With this project we want to provide new insight into autoimmunological pathomechanisms on the metabotropic receptor mGluR5 as well as on the link between tumor and autoimmunity. A better understanding of the pathophysiology may modify treatment strategies and serve patients with autoimmune encephalitis in general.
Dr. med. Daniel Nörenberg
Charité – Universitätsmedizin Berlin, Medical Department, Division of Hematology, Oncology and Tumor Immunology
Email: daniel.noerenberg@charite.de
Fields of Research
- Lymphoma Genetics
- Lymphomagenesis
- Clonal Hematopoiesis and Preleukemia
Project Title
Genetic Characterization of Primary Mediastinal B-Cell Lymphoma
Project Description
Accounting for approximately 10% aggressive lymphomas and ~2% of newly diagnosed Non-Hodgkin lymphoma (B-NHL) cases, primary mediastinal B cell lymphoma (PMBL) is a relatively rare disease. It mainly affects young and otherwise healthy women. Although important treatment improvements could be achieved in the last years, a significant proportion of patients remain refractory to standard immunochemotherapy or relapse within a short time period. As PMBL has previously not been distinguished from DLBCL, there is a large knowledge gap regarding its underlying genetic alterations and the prognostic and predictive importance of recurrent gene mutations. As shown by our recent work, unraveling genetic aberrations underlying PMBL lymphomagenesis has the potential to identify new targets for tailored therapy approaches. A thorough description of the mutational spectrum in PMBL and the identification of key oncogenic drivers will thus facilitate rational therapeutic approaches. Until now, we have collected the world’s largest PMBL cohort (n>350) through national and international collaborations comprising clinically well-annotated patients. Using a combination of whole-exome, targeted deep resequencing, and gene expression analysis, we aim to identify key oncogenic drivers and deregulated signaling pathways in PMBL. Based on the previous molecular analyses, functional consequences of candidate driver mutations will be analyzed in PMBL cell lines using the CRISPR/Cas technology.
PD Dr. med. Sebastian Ochsenreither
Dr. med. Christian Oeing
Charité – Universitätsmedizin Berlin, Department of Cardiology, Angiology and Intensive Care / German Heart Center Berlin at Charité
Email: Christian.oeing@dhzc-charite.de
Fields of Research
- Heart Failure
- Onco-Cardiology
- Molecular Cardiology
Project Title
Fine-Tuning the TSC2-MTOR Axis in Diabetic Cardiomyopathy
Project Description
Diabetes mellitus (DM) is linked with heart failure even after controlling for coronary artery disease and hyper-tension. This type of heart failure is called diabetic cardiomyopathy (DM-CMP). DM-CMP has become an increasingly recognized entity among clinicians, hence a better understanding of its pathophysiology is necessary for diagnosis and treatment strategies. Mammalian (mechanistic) target of rapamycin (mTOR) has been shown to be a key marker of diabetic cardiomyopathy, and inhibiting mTOR has been shown to be beneficial in diabetic hearts. Nevertheless, it is known that broad inhibition of mTOR has major side effect including immunosuppression. Therefore, more targeted fine-tuning of mTOR signaling is necessary. This project determines the mechanisms and therapeutic implications of our new discovery that cGMP-stimulated protein kinase (PKG) suppresses mTOR complex 1 (mTORC1). mTOR is a master regulator of protein and lipid synthesis, metabolism, and autophagy in response to growth factors including insulin, as well as to metabolites, and mechanical load. Its activation favors growth while reducing autophagy, and is thought to play key roles in heart failure, cancer, aging, diabetes, and others. Our data shows that PKG stimulates autophagy by inhibiting mTOR activity, improving heart function and blocking maladaptive responses to hor-monal and pressure-overload stress. This requires PKG phosphorylation (activation) of tuberin (TSC2), a principal negative modulator of mTOR. We find PKG blunts mTOR by phosphorylating / activating TSC2 at a Serine 1365, enhancing autophagy and countering pathological stress remodeling in vitro and in vivo. This new mechanism is exciting because its impact is substantial when mTOR is being activated, but not under resting conditions allowing more fine-tuning and a new therapeutic toehold that does not have major side effects seen by broad pharmaceutical mTOR inhibition. We now found another pathomechanism that we first test in mice and might lead to a novel clinical trial to improve outcome of patients with heart failure under different metabolic stress conditions.
Dr. med. Lena Oevermann
Charité – Universitätsmedizin Berlin, Department of Pediatrics, Division of Oncology and Hematology
Email: lena.oevermann@charite.de
Fields of Research
- Immune Reconstitution After HSCT
- Innovative Therapies for GvHD
- Biobanking
Project Title
An Immune Reconstitution and Biomarker Platform for Hematopoietic Stem Cell Transplantation in Children
Project Description
Graft versus host disease (GVHD), infections and graft rejection are major complications following hematopoietic stem cell transplantation (HSCT) in children. Severe GvHD is associated with a high mortality rate and re- mains one of the main reasons for mortality after allogeneic HSCT. Graft rejection remains an obstacle to successful transplantation for children with non-malignant diseases, such as ß-thalassaemia or sickle cell disease. Within this project, we established a biobank for an en- during asservation of materials including blood, urine, feces, cerebrospinal fluid, bone marrow and tissue biopsies. Our patient cohort consists of all pediatric patients undergoing HSCT in the Department for Pediatric Hematology/Oncology/SCT at the Charité and their family donors (currently included: 70 patients, 20 family donors). To connect clinical courses and experimental results, all data will be collected and saved in our database. During the first two years after HSCT, immune reconstitution is characterized using flow cytometry (NAVIOS, DuraClone technology) allowing a detailed characterization of T-, B, dendritic- and natural killer cells and their subsets. Our project aims at a better prediction, prevention and innovative therapeutic approaches for GvHD. Therefore, we are currently evaluating mesenchymal stromal cell-derived exosomes as a new therapeutic approach for GvHD. Moreover, we will focus on the investigation of the human intestinal microbiota and its significance in GvHD, aiming to find the optimal preparation strategy before HSCT and perform fecal microbiota transplantation in the future. Functional analyses of both projects will be carried out in a minor mismatch GvHD mouse-model (in cooperation with O. Penack). Findings will be validated in multicenter studies including further pediatric and non-pediatric HSCT centers. Comparing impacts of different transplantation settings on the clinical outcome will support transplantation strategy optimization focussing on individualized immunosuppressive drug choice and dosing. Identification of new therapeutic strategies includes the investigation of GvHD pathophysiology and will allow earlier – pre-transplant, if possible – therapeutic options and thereby help to reduce the incidences of GVHD, infections and graft rejection after HSCT.
Dr. med. Florence Pache
Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology
Email: florence.pache@charite.de
Fields of Research
- Neuroimmunology
- Neuro‐Ophthalmology
- Innate Immunity
Project Title
Neuromyelitis Optica Spectrum Disease as an Example of Autoimmune Encephalomyelitis - Are There Immunological Predictive Factors?
Project Description
During the past decade, much progress has been made in the understanding and in the characterization of inflammatory demyelinating diseases of the central nervous system. The most recent and important achievement along this line was the recognition of myelin-oligodendrocyte glycoprotein anti-body associated encephalomyelitis (MOG-ab-EM) as a new disease entity within the spectrum of inflammatory demyelinating diseases with a broad clinical phenotype (recurrent optic neuritis, ex- tensive transverse myelitis, acute disseminated encephalomyelitis as well as brainstem encephalitis). The objective of this project is to clarify the role of the complement system in MOG antibody-associated encephalomyelitis. We, therefore, built a cohort of NMOSD patients with broad clinical characterization. Although NMOSD is a rare disease by acquiring a relatively large number of patients we were able to identify and analyze a sub- group carrying MOG-ab and study immune parameters. Exemplarily by examining complement factor C4, AQP4- IgG positive NMOSD and MOG-IgG positive NMOSD could be discriminated as two different disease entities: our sample of 19 healthy controls, 24 relapsingremitting multiple sclerosis patients as well as 16 AQP4-IgG and 18 MOG- IgG positive patients shows a significant consumption of the complement component C4 in AQP4-IgG positive patients compared to MOG-IgG positive patients. There was no effect of the covariates age and gender.
Dr. med. Florence Pache
Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology
Email: florence.pache@charite.de
Fields of Research
- Neuroimmunology
- Neuro‐Ophthalmology
- Innate Immunity
Project Title
Neuromyelitis Optica Spectrum Disease as an Example of Autoimmune Encephalomyelitis - Are There Immunological Predictive Factors?
Project Description
During the past decade, much progress has been made in the understanding and in the characterization of inflammatory demyelinating diseases of the central nervous system. The most recent and important achievement along this line was the recognition of myelin-oligodendrocyte glycoprotein anti-body associated encephalomyelitis (MOG-ab-EM) as a new disease entity within the spectrum of inflammatory demyelinating diseases with a broad clinical phenotype (recurrent optic neuritis, ex- tensive transverse myelitis, acute disseminated encephalomyelitis as well as brainstem encephalitis). The objective of this project is to clarify the role of the complement system in MOG antibody-associated encephalomyelitis. We, therefore, built a cohort of NMOSD patients with broad clinical characterization. Although NMOSD is a rare disease by acquiring a relatively large number of patients we were able to identify and analyze a sub- group carrying MOG-ab and study immune parameters. Exemplarily by examining complement factor C4, AQP4- IgG positive NMOSD and MOG-IgG positive NMOSD could be discriminated as two different disease entities: our sample of 19 healthy controls, 24 relapsingremitting multiple sclerosis patients as well as 16 AQP4-IgG and 18 MOG- IgG positive patients shows a significant consumption of the complement component C4 in AQP4-IgG positive patients compared to MOG-IgG positive patients. There was no effect of the covariates age and gender.
PD Dr. med. Alexander Paliege
Charité – Universitätsmedizin Berlin, Medical Department, Division of Nephrology and Internal Intensive Care Medicine
Email: alexander.paliege@ukdd.de
Fields of Research
- Acute Kidney Injury
- Kidney Transplant Rejection
- Anti‐Inflammatory Mediators
Project Title
Regulation of Intrinsic Anti-Inflammatory Mediators During the Rejection of Kidney Transplants
Project Description
Kidney transplantation is the preferred treatment modality for patients with endstage renal disease and improves quality of life and overall survival. Advances in organ allocation, surgical techniques, and immunosuppressant combination strategies have effectively reduced rejection rates and improved 1-year-graft survival to values above 95%. These advances, however, have not translated into a proportionate increase of long-term graft survival. The etiology of premature allograft deterioration is multi-factorial and includes nephrotoxic effects of immunosuppressive drugs and chronic subclinical rejection. Novel methods for the detection of transplant rejection and the development of immunosuppressant drugs with reduced toxicity are therefore necessary to improve long-term outcome after kidney transplantation. The glucocorticoid-inducible protein annexin A1 has been identified as the central mediator of endogenous anti-inflammatory signaling pathways. It may, therefore, promote the resolution of renal inflammation and foster tissue repair. The regulation of annexin A1 during renal transplant rejection has not been characterized. The aim of the first part of the project is to study the expression of annexin A1 in kidney biopsies from patients with transplant rejection and to identify cellular sources and potential targets for anti-inflammatory annexin A1 signals. The second part of the project will determine the utility of annexin A1 as a biomarker for the detection of renal transplant rejection.
Dr. med. Yannick Palmowski
Charité – Universitätsmedizin Berlin, Center for Musculoskeletal Surgery
Email: yannick.palmowski@charite.de
Fields of Research
- Spinal surgery
- Osteology
Project Title
Evaluation of the Validity of New Methods for the Assessment of Bone Quality Using Vertebral Biopsies
Project Description
In osteroporosis, changes in bone composition and structure result in reduced bone stability. In orthopedic surgery, such a »weak« bony bearing represents a significant challenge intraoperatively and can have serious consequences for affected patients due to resulting implant failure. To avoid such complications, preoperative diagnostics are necessary to allow the timely initiation of adequate therapeutic measures (e.g., cement augmentation). However, reliable methods that allow preoperative prediction of intraoperative findings are still lacking. The current clinical standard for the assessment of bone quality is Dual Energy X-ray Absorptiometry (DXA), which measures the mineralization density of bone using 2D X-ray projections. In a previous study, we demonstrated that DXA is unsuitable for assessing bone quality at the lumbar spine. In this research project, we therefore want to examine whether the alternative methods Trabecular Bone Score (TBS) or Bone Material Strength index (BMSi) reflect the actual bone quality at the lumbar spine determined on the basis of vertebral body biopsies and whether they are suitable for assessing the risk of material loosening after spinal surgery.
Dr. med. Livius Penter
Charité – Universitätsmedizin Berlin, Medical Department, Division of Hematology, Oncology and Tumor Immunology
Email: livius.penter@charite.de
Fields of Research
- Rectal Cancer
- Tumor Immunology
Project Title
Immunologic Biomarkers and Therapeutic Targets in Rectal Cancer
Project Description
Early disease and relapse detection are critical for colorectal cancer prognosis. However, the reliable identification of relapse can be challenging, especially if the suspected tumorous lesions are small in size and/or not easily accessible, underlining the need for highly specific and sensitive biomarkers. Most of the established tumor markers are not cancer-specific and show poor sensitivity for relapse detection varying between 15 and 70%. There is increasing evidence that tumor-infiltrating (immune) cells are critical for disease development, spread- ing, and patient survival and frequencies of tumor-infiltrating lymphocytes (TILs) correlate with the clinical outcome regardless of the tumor stage. Our group could show that colorectal cancer is infiltrated with T lymphocytes of a highly specialized T cell receptor (TCR) repertoire and distinct functions suggesting a tumor-driven T cell reaction. Therefore, technologies for cancer (-relapse) detection could significantly benefit from the inclusion of disease-associated immune measurements. This study will result in a phenotypic, functional, and molecular immunology approach to the human immune system in rectal cancer. Emerging technologies including cytometry by time-of-flight (CyTOF) and single cell next-generation sequencing (NGS) will help to detect cancer-associated immune responses as a highly specific and sensitive immune-biomarker. We hypothesize that unique rectal cancer-associated, clonally related T lymphocytes are detectable in the tumor tissue and peripheral blood of patients and that their frequencies correlate with disease burden which makes them useful as immune biomarkers for early relapse detection. Selectively expand- ed T cell clones and phenotypes can be quantified and possibly used as highly sensitive and specific cancer-associated markers for therapy monitoring and early relapse detection.
Dr. med. Lennart Pfannkuch
Charité – Universitätsmedizin Berlin, Medical Department, Division of Infectiology and Pneumonology
Email: lennart.pfannkuch@charite.de
Fields of Research
- Innate Immunity
- Helicobacter Pylori
- Signal Transduction
Project Title
Characterization of a Pro-Inflammatory Pathway Triggered by Bacterial Sugar Molecule
Project Description
Activation of the transcription factor NF-κB is a linchpin in the initiation of an inflammatory process in cells of the adaptive and innate immune response. Chronic or inadequate activation can lead to deleterious outcomes like the development of cancer. In 2015, a bacterial sugar, D-glycero-beta-D-mannoheptose 1,7-bisphosphate (HBP), an intermediate metabolite of LPS synthesis, was identified as novel Pathogen Associated Molecular Pattern (PAMP) inducing NF-κB activation in epithelial cells. In a Helicobacter pylori (H. pylori) infection model we have recently identified a HBP triggered NF-κb activating signaling axis. We demonstrated that HBP is delivered via H. pylori’s Type 4 Secretion System to the host cell. Here ALPK1 and TIFA act as indispensable host cell factors for the early activation of NF-κB. This renders ALPK1 a central infection specific actor in activating a pro-inflammatory signaling pathway. The general importance of this pathway is underlined by the fact that HBP has already been identified as a pro-inflammatory factor in a row of infections with gramnegative bacteria making this a likely candidate for induction of a pro-inflammatory response in a multitude of infectious settings. Yet the exact function of the ALPK1 in the activation of this pathway is not yet understood. Aim of this project is to get a deeper insight in this novel-signaling axis, under- standing the way of induction and the regulatory mechanisms it induces and additionally deciphering how HBP is sensed in infected cells. Finally, with this project we want to understand the impact of ALPK1 on the outcome of an infection in vivo.
PD Dr. med. Constanze Pfitzer
German Heart Center Berlin, Department of Congenital Heart Disease, Pediatric Cardiology
Email: constanze.pfitzer@dhzc-charite.de
Fields of Research
- Neurological Outcome of Children and Grown‐Ups with Congenital Heart Disease
- Hypothermia
Project Title
»Of Heart and Mind«: A Longitudinal Neuropsychological Evaluation of Children with Congenital Heart Disease
Project Description
Neurodevelopmental deficits are the most common, and potentially most disabling long-term complications for patients with congenital heart disease (CHD) and their treatment. However, only a few studies have investigated the development of the child longitudinally. That is why we would like to test these patients using different neurological and developmental tests. This prospective longitudinal study evaluates the neuropsychological outcome of children who had a heart operation in the new- born or infant age. Project 1: Common CHD: This patient group includes children with common CHD who required an operation in the new-born and infant period, i.e.: patients who had an arterial switch operation with trans- position of the great arteries (TGA), as a common operation in the new-born period; children who had an operation of a ventricular septal defect (VSD) as the most common CHD; and children with surgical repair of a tetralogy of Fallot (TOF) as a cyanotic CHD. Project 2: Resuscitation and mechanical circulation support: Included is patients who had a resuscitation (longer >five minutes) and an implantation of an extracorporeal membrane oxygenation and ventricular assist device. The central measurement instrument is the Bayley Scales of Infant Development, which is a pediatric development test and consists of a series of developmental play tasks used to derive a developmental quotient. The patients will be tested at the age of one, two and three years. In summary, we would like to evaluate the neuropsychological development of children after surgical repair of a TOF, VSD or TGA, compare it to the normal development of children, and determine if there are differences between these patient groups. Finally, we will study the neuropsychological development of children after resuscitation and mechanical circulation support.
Dr. med. Constanze Pfitzer
German Heart Center Berlin, Department of Congenital Heart Disease, Pediatric Cardiology
Email: pfitzer@dhzb.de
Fields of Research
- Neurological Outcome of Children and Grown‐Ups with Congenital Heart Disease
- Hypothermia
Project Title
»Of Heart and Mind«: A Longitudinal Neuropsychological Evaluation of Children with Congenital Heart Disease
Project Description
Neurodevelopmental deficits are the most common, and potentially most disabling long-term complications for patients with congenital heart disease (CHD) and their treatment. However, only a few studies have investigated the development of the child longitudinally. That is why we would like to test these patients using different neurological and developmental tests. This prospective longitudinal study evaluates the neuropsychological outcome of children who had a heart operation in the new- born or infant age. Project 1: Common CHD: This patient group includes children with common CHD who required an operation in the new-born and infant period, i.e.: patients who had an arterial switch operation with trans- position of the great arteries (TGA), as a common operation in the new-born period; children who had an operation of a ventricular septal defect (VSD) as the most common CHD; and children with surgical repair of a tetralogy of Fallot (TOF) as a cyanotic CHD. Project 2: Resuscitation and mechanical circulation support: Included is patients who had a resuscitation (longer >five minutes) and an implantation of an extracorporeal membrane oxygenation and ventricular assist device. The central measurement instrument is the Bayley Scales of Infant Development, which is a pediatric development test and consists of a series of developmental play tasks used to derive a developmental quotient. The patients will be tested at the age of one, two and three years. In summary, we would like to evaluate the neuropsychological development of children after surgical repair of a TOF, VSD or TGA, compare it to the normal development of children, and determine if there are differences between these patient groups. Finally, we will study the neuropsychological development of children after resuscitation and mechanical circulation support.
Dr. med. Sylvie Picker-Minh
Charité – Universitätsmedizin Berlin, Department of Pediatrics, Division of Neurology
Email: sylvie.minh@charite.de
Fields of Research
- Microcephaly
- Brain Development
- Rare Diseases
Project Title
Identification and Characterization of »Novel« Microcephaly Genes
Project Description
Reduced brain volume manifesting as microcephaly (MC) is often associated with intellectual disability (ID) and further comorbidities. With this project, we aim to characterize further genetic causes of MC and ID and to better understand underlying pathomechanisms. In a first part of the project, we aim to identify novel microcephaly genes by a process of clinical screening and genetic analysis of patients with a novel ID/MC phenotype. In a second part of the project, we focus on the functional analysis of novel microcephaly genes identified in our research group. Here, we address the infantile multisystem neurologic, endocrine and pancreatic disease (IM- NEPD), recently first described by our research group and linked to homozygous mutations in the peptidyl-tRNA hydrolase 2 (PTRH2) gene. IMNEPD is a multisystem disease with neurological features of intellectual disability, postnatal microcephaly, and cerebellar atrophy. Ptrh2 is an evolutionarily well-conserved protein, which prevents accumulation of peptidyl-tRNAs and thereby maintains protein synthesis. Ptrh2 furthermore has a key role in the regulation of anoikis, a process defined as cell death caused by loss of cell attachment to the extracellular matrix. Our research group also showed that Ptrh2 plays a role in cell size regulation of neurons, skeletal muscle cells, liver and pancreas cells. We have generated Ptrh2 knockout mice and analyzed the role of PTRH2 in brain development in vivo and in vitro.
PD Dr. med. Daniel Pilger, MSc
Charité – Universitätsmedizin Berlin, Department of Ophthalmology
Email: daniel.pilger@charite.de
Fields of Research
- Corneal Dystrophy
- Corneal Surgery
- Oculoplastic Surgery
Project Title
Femtosecond Laser Assisted versus Manual Descemetorhexis
Project Description
Posterior lamellar keratoplasty such as Descemet membrane endothelial keratoplasty (DMEK) and Descemet stripping automated endothelial keratoplasty (DSAEK) has become the standard treatment for conditions like Fuchs` endothelial dystrophy. In DMEK surgery, the patient’s dysfunctional endothelial layer is replaced with a donor Descemet membrane (DM). A key step during DMEK surgery is the descemetorhexis (DR), the excision of the recipient’s DM. The surgeon penetrates the anterior chamber and makes a circular incision into the patient’s DM prior to removing it. Femtosecond laser technology is an important technological advance in ophthalmic surgery. In combination with computer-controlled optical delivery systems, femtosecond lasers are capable of producing precise surgical incisions without damaging surrounding tissues. Thus far, femtosecond lasers have been mainly used in cataract surgery. We have developed a novel method, femtosecond laser-assisted DR, to facilitate DMEK surgery. In a clinical trial, we are investigating possible benefits and the safety of this new procedure in DMEK surgery.
Dr. med. Julian Pohlan
Charité – Universitätsmedizin Berlin, Department of Radiology (including Pediatric Radiology)
Email: julian.pohlan@charite.de
Fields of Research
- Thermoablation
- CT-Thermography
- Dual-energy computed tomography
Project Title
CT-Thermography for Intraprocedural Ablation Zone Monitoring
Project Description
Using density data routinely acquired by computed tomography but neglected so far, it is now possible to provide an estimate on tissue temperature during thermoablation for operator feedback. Previous experiments in ex vivo porcine liver tissue indicated that heat ablation yields more accurate temperature estimates than cryoablation. Current challenges include the optimized coregistration of images in order to reduce breathing artifacts in the living animal. We are working on CT Thermography to improve the quality of thermoablation especially in renal cell carcinoma and thereby fight local recurrence.
Professional Experience
0Dr. med. Wolfram Poller
Charité – Universitätsmedizin Berlin, Medical Department, Division of Cardiology and Angiology
Email: wolfram.poller@charite.de
Fields of Research
- Atherosclerosis
- Inflammation and Glycosaminoglycans
- Nanoparticle Imaging
Project Title
Glycosaminoglycans as Targets for Non-Invasive Imaging of Unstable Atherosclerotic Plaques
Project Description
Atherosclerotic plaque ruptures cause life-threatening complications including myocardial infarction and stroke. Methods to identify unstable plaques prior to rupture are therefore highly desirable. Proteoglycans (PG) and their glycosaminoglycan (GAG) chains are key components of the extracellular matrix in atherosclerotic plaques and are involved in disease progression. It is currently unknown whether plaque instability correlates with a specific PG/GAG pattern. This project aims at the identification of instability-associated PG/GAG and their use as targets for non-invasive imaging. We will comparatively analyze PG/GAG composition, GAG structure and their chemical modifications in stable and unstable human atherosclerotic lesions from the coronary and carotid arteries. Glycoanalytical techniques (HPLC, CE-LIF, MALDI-im- aging) as well as histological- and expression analyses (RT-PCR, Western Blot, IHC, TEM, FISH) will be applied to identify instability-associated PG/GAG as novel targets for non-invasive imaging of unstable plaques. Previous experiments demonstrated that i.v.-injected citrate-coated very small superparamagnetic iron-oxide nanoparticles (VSOP) are rapidly taken up by atherosclerotic lesions, thereby enabling plaque visualization in the MRI. Experiments in cell culture models and rodents led to the hypothesis that VSOP primarily binds to GAG components of unstable plaques. To prove this hypothesis, we will analyze the potential of VSOP-based MRI to identify unstable atherosclerotic plaques in comparison with established invasive methods including intravascular ultrasound (IVUS) and optical coherence tomography (PCT). These experiments will be performed in Göttingen minipigs under high-fat diet and streptozotocin-induced diabetes.
Dr. med. Uwe Primessnig, PhD
Charité – Universitätsmedizin Berlin, Department of Internal Medicine and Cardiology
Email: uwe.primessnig@charite.de
Fields of Research
- Interventional cardiology
- Cellular mechanisms of contractile dysfunction and arrhythmias
Project Title
Sudden Cardiac Death, Arrhythmias and Cardiac Contractile Dysfunction in HFpEF
Project Description
Heart failure with preserved ejection fraction (HFpEF) is an increasingly common syndrome with poor prognosis, high mortality and morbidity. Sudden cardiac death (SCD) is the most common mode of death in HFpEF (26% SCD in I-Preserve and 24.3% in TOPCAT. However, the pathogenesis of sudden cardiac death in this patient population is not well-understood. The major aims of the project are to investigate underlying cellular causes of contractile dysfunction and calcium mediated arrhythmias in cardiorenal and metabolic HFpEF.
Dr. med. Vincent Prinz
Prof. Dr. med. Magdalena Sarah Prüß
Charité – Universitätsmedizin Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology
Email: magdalena.pruess@charite.de
Fields of Research
- Gastroenterology
- Chronic Pain
- Immune System
Project Title
Functional Brain Changes and Pain Reduction in Patients with Inflammatory Bowel Disease
Project Description
Inflammatory bowel diseases (IBD) are associated with chronic pain in up to 38% of patients. Chronic pain conditions such as neuropathic pain have previously been shown to result in functional and structural changes in both the peripheral and the central nervous system (CNS). Those so-called maladaptive changes are described as the phenomena of hyperexcitability and hypersensitivity. Recently published work suggests an interaction be- tween the central and the enteric nervous system (ENS). Visceral pain in chronic pancreatitis has been associated with an inflammatory infiltration of pancreatic perineuria that includes macrophages, T-cells, and mast cells. We have previously shown that transcranial direct current stimulation (tDCS), a non-invasive method to transcranial modulate neuronal plasticity, is efficient to treat pain in IBD patients (Prüß/Volz et al., Pain 2016). Since the impact of tDCS on the CNS of IBD patients as well as putative effects on the mucosal immune system via activation of the ENS have not been studied yet, we aim to analyze the brain-gut axis by performing a prospective clinical phase-III-trial: tDCS will be applied to IBD patients to ameliorate IBD-associated pain. In parallel, the impact of tDCS on CNS structure and function (fMRI) as well as IBD disease activity and the dynamics of immune cell activity (mucosal and in peripheral blood samples) will be studied in patients before and after tDCS treatment. Finally, in search of the mechanistic link between stimulation of the CNS and mucosal inflammation, we will switch to a mouse model of colitis-associated chronic visceral pain. This will allow to address the interrelation of CNS, ENS, neurotransmitters production and mucosal inflammation and to study underlying mechanisms by assessing the role of a distinct set of neurotransmitters as well as the contribution of inflammatory cellular infiltrates. With this approach, we aim to decipher mechanistic insights of the gut-brain-axis and hence identify novel therapeutic targets.
Dr. med. Judith Rademacher
Charité – Universitätsmedizin Berlin, Medical Department, Division of Gastroenterology, Infectiology and Rheumatology
Email: judith.rademacher@charite.de
Fields of Research
- Acute Anterior Uveitis
- Axial Spondyloarthritis
- Biomarkers
Project Title
Early Recognition of Axial Spondyloarthritis in Patients with Acute Anterior Uveitis: Establishing and Validation of an Early Referral Tool
Project Description
The diagnostic delay in axial spondyloarthritis (axSpA) still remains high at around nine years. Early diagnosis in axSpA is especially relevant as short disease duration is one of the best predictors of good clinical response to therapeutic treatment and the halt of radiographic progression. The major barrier for early diagnosis in axSpA is a late referral of patients to rheumatologists. Acute anterior uveitis is a common extra-articular axSpA manifestation as more than 20% of patients with axSpA develop in the course of their disease and vice versa, 20- 40% of the patients with acute anterior uveitis suffer from axSpA. In many of them, the disease is not recognized when the first uveitis episode occurs. Recently, the Dublin Uveitis Evaluation Tool (DUET) for detection of undiagnosed spondyloarthritis in patients presenting with acute anterior uveitis was proposed by Haroon et al. (Ann Rheum Dis 2015) consisting of three steps (ques- tion about back pain, HLA-B27 test and psoriasis evaluation). With this study, we are analyzing whether an early recognition of patients with high probability of axSpA among patients with acute anterior uveitis is possible if an adaption of the Assessment of SpondyloArthritis International Society (ASAS) referral tool (Poddubnyy et al, Ann Rheum Dis 2015) is applied on the level of ophthalmologists. Following the ASAS referral tool, all patients with acute anterior uveitis and chronic back pain (> 3 months) with a beginning before 45 years should be referred to a rheumatologist. Thus, the ASAS tool might be more applicable for ophthalmologists who do not have the possibility of HLA-B27 testing or psoriasis evaluation. The performance of this ASAS referral tool will then be compared to the DUET. Moreover, we have extended the referral study to an inception cohort and will thus monitor patients with the history of acute anterior uveitis with and without axSpA over a period of up to ten years. We hope to gain a deeper insight into the disease’s course with this inception cohort.
Dr. med. Josefine Radke
Charité – Universitätsmedizin Berlin, Department of Neuropathology
Email: josefine.radke@charite.de
Fields of Research
- Primary Central Nervous System Lymphoma
- Lymphomagenesis
- Brain Tumors
Project Title
Molecular Genetic Analysis and Preclinical Modeling of CNS Lymphoma
Project Description
Despite extensive research, the molecular alterations leading to primary central nervous system lymphoma (PCNSL) and the reasons why PCNSL are confined to the CNS have not been fully elucidated. With regard to the genetic alteration of PCNSL, available data are restricted to whole exome and Sanger sequencing. Our research effort shall gain more insight into the molecular landscape of PCNSL. So far, we assembled a unique collection of 36 CNS lymphoma specimen and used WGS, RNseq and DNA methylation arrays (850K arrays) to identify important, prognostically relevant genetic and epigenetic alterations and to distinguish between »driver mutations« (e.g. MYD88, CD79B, CARD11, KMT2D, and CD- KN2A/B) and kataegis events (e.g. PIM1, BTG2, OSBL10). The results have been compared to the signatures of DLBCL without CNS manifestation (pDLBCL) to identify differences between both entities. Our RNAseq results have already shown separate clustering of PCNSL and pDLBCL and clear differences in terms of expression levels of many different genes involved in e.g. immune escape and response (e.g. HLA-DR, PD-L1, TLRs). Additionally, we seek to elucidate the protein landscape of PCNSL by mass spec. So far, reverse phase protein array (RPPA) revealed high expression of many cancer related (phos- pho-)proteins in PCSNL, e.g. BTK or MAPK which could be possible targets for tyrosine kinase inhibitors. For further validation, preclinical modeling, and drug target development, we use 3 different diffuse large B-cell lymphomas (DLBCL) cell lines (U2932, OCI-Ly3 und OCI- Ly7) to perform differently in vitro anticancer experiments, e.g. chemical inhibition of MYD88 homodimerization.
Dr. med. Bianca Raffaelli
Charité – Universitätsmedizin Berlin, Department of Neurology and Experimental Neurology
Email: bianca.raffaelli@charite.de
Fields of Research
- Migraine
- Sex hormones
Project Title
Plasma CGRP Levels in Patients with Migraine and Endometriosis
Project Description
Migraine and endometriosis are two of the most prevalent disorders in women with a significant burden of disease, high socioeconomic costs, and a relevant impairment of quality of life. Epidemiological studies report a solid comorbidity between migraine and endometriosis. From adolescence onwards, women with endometriosis have a two- to threefold higher risk of suffering from migraine compared to the general female population, and vice versa, patients with migraine have a twice higher probability to develop endometriosis. Fluctuations in ovarian sex hormones modulate the course of both diseases and severe pain attacks occur often during the perimenstrual period. Previous research pointed to a possible common etiological background for migraine and endometriosis. Shared pathophysiological mechanisms include impaired regulation of inflammatory signaling pathways and neurotransmitters such as Calcitonin Gene-Related Peptide (CGRP). While acute migraine is clearly linked to CGRP release from trigeminal afferent neurons during attacks, the evidence for a role of CGRP in endometriosis pain is limited. The release of CGRP seems to have an impact on the neurogenic inflammatory reaction in this endometriosis tissue and might be also involved in proliferation and growth of endometriotic cells. Despite these findings, CGRP and CGRP-related mechanisms have not been studied to date in vivo in women with endometriosis. In the current project, we aim to analyze CGRP plasma concentrations in patients with migraine and endometriosis, compared to patients with migraine only, endometriosis only, and healthy controls. For each group, we will compare CGRP concentrations during menstruation and in the intermenstrual period. It is our hypothesis that CGRP levels increase during menstruation with most pronounced changes in women with the comorbidity of migraine and endometriosis.
PD Dr. med. Bernhard Ralla
Charité – Universitätsmedizin Berlin, Department of Urology
Email: bernhard.ralla@charite.de
Fields of Research
- Renal Cell Carcinoma
Project Title
Prediction of Primary Resistance to First-Line Treatment with the Tyrosine Kinase Inhibitor Sunitinib in Renal Cell Carcinoma Specimens by miRNA Profiles
Project Description
The introduction of targeted therapy agents has significantly improved the overall survival (OS) of patients with metastatic renal cell carcinoma (mRCC). The VEGF-inhibitor sunitinib (sun) is considered the standard of care for the first-line treatment of these patients, however, the tumor response to this drug at first evaluation is crucial. Patients with a primary resistance inherit a poor overall survival. A reliable prediction of the primary resistance to sun therapy could be helpful to avoid useless treatment trials of patients with extremely expensive drugs and to save time to select other therapeutic options. So far, there has been no approved biomarker in form of a companion diagnostic test to correctly predict the response to targeted therapy in these patients. In this regard, microRNAs (miRNAs, miRs) as small, non-protein coding transcripts could be considered as suitable biomarkers be- cause of their important role as posttranscriptional regulators in all network processes of carcinogenesis and metastasis. So, the aims of this study were (a) to identify typical microRNA profiles in nephrectomy specimens from the two groups of mRCC patients under sunitinib treatment, (b) to explore under high statistical power the most discriminative microRNAs between the two patient groups as predictive biomarkers of primary resistance and (c) to validate the data quantified by reverse transcription quantitative polymerase chain reaction (RT-qPCR) additionally through sophisticated digital PCR technique and decision curve analysis in comparison to conventional clinico-pathological variables.
Dr. med. Mirja Ramke
Charité – Universitätsmedizin Berlin, Medical Department, Division of Infectiology and Pneumonology
Email: mirja.ramke@charite.de
Fields of Research
- Machine Learning/AI
- Influenza Pneumonia
- Infectious Disease
Project Title
Viral/Bacterial Co-Infection in Pneumonia – How to Better Understand the Deadly Liaison
Project Description
Towards a machine learning based approach for combining microscopic images with molecular profiling data to predict the regulatory network of inflammation on a cellular level. During the 1918 influenza A virus (IAV) pandemic, more than 50 million individuals died from pneumonia. Among them, bacterial co-infections, in particular those with Streptococcus pneumoniae (S.pn.) or Staphylococcus aureus (S.a.), dramatically complicated the initial viral threat. This deadly liaison of an initial IAV infection followed by a subsequent bacterial infection is still significantly contributing to the high mortali- ty rate of 10-15 %, which has not been changed since the introduction of antibiotics. Moreover, considering the threat of future IAV outbreaks and the increasing bacterial resistance towards antibiotics, it is pivotal to deeper apprehend the molecular and cellular interplay between viruses, bacteria, and pulmonary target cells to enable innovative adjunctive therapies beyond pathogendirected clinical approaches. Over the last decade, both, molecular profiles from »omics« data sets as well as advanced microscopic imaging were able to significantly improve our understanding of the inflammatory response in many disease areas. Although both technical approaches show major contributions, they cannot easily be combined yet. So far, microscopy just allows for studying inflammatory processes with a distinct cellular localization with high spatial resolution of selected factors. The other way round, »omics« data sets re- veal genome wide molecular profiles of the samples, but without any kind of cellular assignment. Thus, it would be of great benefit if the molecular profiles of normal and diseased tissues could be predicted into the in situ cellular context revealed by advanced microscopic imaging. Therefore, we aim to establish a machine learning based approach that identifies the spatial/morphological features that are statistically associated with the respective gene expression to predict the regulatory network of inflammation on a cellular level.
PD Dr. med. Nathanael Raschzok
Charité – Universitätsmedizin Berlin, Department of Surgery
Email: nathanael.raschzok@charite.de
Fields of Research
- Liver Transplantation
- Liver Tissue Engineering
- Liver Regeneration
Project Title
Defatting of Steatotic Liver Grafts by Ex Vivo Machine Perfusion with DNP
Project Description
Liver transplantation is the treatment of choice for patients with advanced liver cirrhosis, non-metastatic early hepatocellular carcinoma, and severe metabolic or autoimmune hepatic disorders. While the need for liver grafts is continuously rising, the number of available do- nor organs is increasingly limited by the scarcity of suit- able donor organs. Steatotic liver grafts from donors with fatty liver disease pose a certain risk of primary non-function to the recipient. Defatting by ex vivo machine perfusion has already been proposed as a strategy for conditioning of steatotic liver grafts. A significant reduction of the liver fat could already be achieved by ex vivo perfusion of steatotic rat and pig livers with defatting agents, but successful transplantation of defatted grafts has not yet been shown. This project aims to establish a concept for defatting of steatotic liver grafts by ex vivo machine perfusion with 2,4-Dinitrophenol (DNP) in a rat liver transplantation model. DNP is a mitochondrial protonophore that shuttles protons across biological membranes. It is hypothesized that DNP is a suitable agent for liver defatting by ex vivo machine perfusion under normothermic or sub-normothermic conditions. Liver fat is metabolized by the increased cellular activity that is needed to compensate for the decreased efficiency of the uncoupled respiratory chain. In a first work package, the already established lab-scaled liver perfusion system was be optimized in order to enable liver perfusion over a period of 6 hours without serious damage to the organ at normothermic. In work package 2, a protocol for liver defatting with DNP is currently developed, with optimal DNP concentration and perfusion time. In work package 3, the safety and feasibility of ex vivo liver defatting and the expected superior outcome after transplantation will be proven in rats in comparison to non-treated steatotic grafts.
PD Dr. med. Dr. med. dent. Carsten Rendenbach
Charité – Universitätsmedizin Berlin, Department of Oral and Maxillofacial Surgery
Email: carsten.rendenbach@charite.de
Fields of Research
- Biomechanics
- Biomaterials
- Mandible Reconstruction
Project Title
Optimizing Free Flap Mandible Reconstruction
Project Description
Mandible reconstruction with osseous free flaps is challenging, especially in patients with oral squamous cell carcinoma and osteoradionecrosis. Currently, titanium is the standard material for osteosynthesis in trauma and reconstructive surgery. In head and neck cancer patients, the metallic characteristics and available plate designs with high bone-areas and extreme stiffness are unfavorable, as they cause severe imaging artifacts in tumor aftercare examinations, interference with radio- therapy and high rates of soft tissue complications, e.g. , plate removal and thus a second surgery is usually necessary. Despite high precision planning, osseous non- union in the interosteotomy gaps is a common problem. With the current project, we evaluate various aspects of mandible reconstruction in order to improve patient outcome. Experimental artifact reduction in CT and MRI imaging, biomechanical characteristics in load-bearing situations in vitro and finite element analyses and magnesium degradation in a long-term animal study are performed in order to validate these biomaterials for potential use in craniomaxillofacial surgery. Additionally, mechanobiological optimizations for mandible fixation systems will be performed in future work packages in cooperation with the Julius-Wolff-Institute for Biomechanics and musculoskeletal regeneration.
Dr. med. Damian Tobias Rieke
Charité – Universitätsmedizin Berlin, Medical Department, Division of Hematology and Oncology
Email: damian.rieke@charite.de
Fields of Research
- Targeted Therapy
- Precision Oncology
- Tumor Inflammation
Project Title
Analysis of Inflammatory Mutational Profiles in Squamous Cell Carcinomas of the Head and Neck
Project Description
The treatment of tumors guided by specific molecular aberrations is expected to increase efficacy whilst limit- ing toxicity. The proof-of-concept of this precision oncology approach was done in several tumor types. We are currently working on the implementation of a bio- marker-guided therapy in clinical routine within the molecular tumor board. Patients with advanced cancers and comprehensive molecular data of their tumors are discussed in this board on a weekly basis to inform targeted treatment.In addition to targeted therapies, immune checkpoint inhibition has revolutionized cancer treatment over the last years. This therapy is based on the enhancement of T-cell mediated anti-tumor efficacy. However, effective biomarkers to guide immune check- point inhibitors are lacking to date. Others and we have shown that specific mutational profiles are associated with differential immunogenic properties of the tumors. We are currently working on the characterization of these properties with a focus on squamous cell carcinomas of the head and neck. To achieve this aim, available datasets of exome- and transcriptome data from head and neck squamous cell carcinomas are analyzed bioinformatically. The created hypotheses are then validated immunohistochemically, in single-cell analyses data as well as clinical cohorts. The ultimate goal of this work is the implementation of biomarkers to guide the use of immune checkpoint inhibition within a precision oncology approach that we have already established. We are thus trying to improve the interpretation of comprehensive molecular tumor data to guide the treatment of patients with advanced cancers.
Dr. med. Damian Tobias Rieke
Charité – Universitätsmedizin Berlin, Medical Department, Division of Hematology and Oncology
Email: damian.rieke@charite.de
Fields of Research
- Targeted Therapy
- Precision Oncology
- Tumor Inflammation
Project Title
Analysis of Inflammatory Mutational Profiles in Squamous Cell Carcinomas of the Head and Neck
Project Description
The treatment of tumors guided by specific molecular aberrations is expected to increase efficacy whilst limit- ing toxicity. The proof-of-concept of this precision oncology approach was done in several tumor types. We are currently working on the implementation of a bio- marker-guided therapy in clinical routine within the molecular tumor board. Patients with advanced cancers and comprehensive molecular data of their tumors are discussed in this board on a weekly basis to inform targeted treatment.In addition to targeted therapies, immune checkpoint inhibition has revolutionized cancer treatment over the last years. This therapy is based on the enhancement of T-cell mediated anti-tumor efficacy. However, effective biomarkers to guide immune check- point inhibitors are lacking to date. Others and we have shown that specific mutational profiles are associated with differential immunogenic properties of the tumors. We are currently working on the characterization of these properties with a focus on squamous cell carcinomas of the head and neck. To achieve this aim, available datasets of exome- and transcriptome data from head and neck squamous cell carcinomas are analyzed bioinformatically. The created hypotheses are then validated immunohistochemically, in single-cell analyses data as well as clinical cohorts. The ultimate goal of this work is the implementation of biomarkers to guide the use of immune checkpoint inhibition within a precision oncology approach that we have already established. We are thus trying to improve the interpretation of comprehensive molecular tumor data to guide the treatment of patients with advanced cancers.
Dr. med. Paul Ritschl, PhD
Charité – Universitätsmedizin Berlin, Department of Surgery
Email: paul.ritschl@charite.de
Fields of Research
- Transplant Immunology
- Ischemia Reperfusion Injury
- Organ Allocation
Project Title
The Impact of Passenger Leukocyte Migration Following Solid Organ Transplantation
Project Description
Following solid organ transplantation, leukocyte migration and trafficking through the recipient ́s body and subsequent allorecognition are the prerequisites for the development of an alloimmune response. Trafficking of leukocytes through blood or lymphatic vessels, as well as their migration in lymphoid or solid organs, is critical for antigen presentation initiating either allograft rejection or mediating allograft acceptance (tolerance). In general, the current understanding of alloantigen recognition by the recipient’s immune system ultimately shaping the specific graft rejection mechanism implies two forms of donor antigen recognition that are defined by the source of APC: during »direct« presentation donor-derived cells display donor major histocompatibility complex (MHC) molecules to the recipient, whereas during »indirect« presentation donor-derived antigens are acquired by recipient APCs that process and present these peptides to the host. Although the direct pathway of allorecognition has been described as playing a tremendous role in initiating the adaptive immune response, antigen recognition in the long-term is attributed to the indirect pathway. During the past decades, the idea that secondary lymphoid organs are supposed to be the major sites of antigen presentation is a widely accepted concept. Key to the following project is the comprehensive analysis of passenger leukocytes, their pathway through the body and the sites of alloantigen recognition by the recipient. Especially lymphatic vessels and their function as »leukocyte highway« will be brought into focus. The fact that surgeons do not reconnect lymphatic drainage of solid organs during transplantation questions tradition- al textbook knowledge but simultaneously offers new scientific possibilities to study passenger leukocytes. What are passenger leukocytes? Does allorecognition solely occur in lymph knots? How does the alloantigen reach the lymph knot? Are there other important sites for initiating transplant rejection?
PD Dr. med. Paul Ritschl, PhD
Charité – Universitätsmedizin Berlin, Department of Surgery
Email: paul.ritschl@charite.de
Fields of Research
- Transplant Immunology
- Ischemia Reperfusion Injury
- Organ Allocation
Project Title
The Impact of Passenger Leukocyte Migration Following Solid Organ Transplantation
Project Description
Following solid organ transplantation, leukocyte migration and trafficking through the recipient ́s body and subsequent allorecognition are the prerequisites for the development of an alloimmune response. Trafficking of leukocytes through blood or lymphatic vessels, as well as their migration in lymphoid or solid organs, is critical for antigen presentation initiating either allograft rejection or mediating allograft acceptance (tolerance). In general, the current understanding of alloantigen recognition by the recipient’s immune system ultimately shaping the specific graft rejection mechanism implies two forms of donor antigen recognition that are defined by the source of APC: during »direct« presentation donor-derived cells display donor major histocompatibility complex (MHC) molecules to the recipient, whereas during »indirect« presentation donor-derived antigens are acquired by recipient APCs that process and present these peptides to the host. Although the direct pathway of allorecognition has been described as playing a tremendous role in initiating the adaptive immune response, antigen recognition in the long-term is attributed to the indirect pathway. During the past decades, the idea that secondary lymphoid organs are supposed to be the major sites of antigen presentation is a widely accepted concept. Key to the following project is the comprehensive analysis of passenger leukocytes, their pathway through the body and the sites of alloantigen recognition by the recipient. Especially lymphatic vessels and their function as »leukocyte highway« will be brought into focus. The fact that surgeons do not reconnect lymphatic drainage of solid organs during transplantation questions tradition- al textbook knowledge but simultaneously offers new scientific possibilities to study passenger leukocytes. What are passenger leukocytes? Does allorecognition solely occur in lymph knots? How does the alloantigen reach the lymph knot? Are there other important sites for initiating transplant rejection?
Dr. med. Susanne Rittig
Charité – Universitätsmedizin Berlin, Department of Hematology, Oncology and Cancer Immunology
Email: susanne-malaika.rittig@charite.de
Fields of Research
- Immunotherapy
- Multiple Myeloma
- Dendritic Cell
Project Title
Augmenting Dendritic Cell Function for Rational Immunotherapies in Multiple Myeloma
Project Description
Multiple Myeloma (MM) is a heterogeneous hematologic malignancy with courses varying from asymptomatic stages to aggressive disease. Despite a plethora of approved therapies the disease largely remains incurable. Hence, novel anti-cancer therapeutic approaches combining efficacy, tolerability and minimal treatment burden are much-needed. Cancer vaccines have shown to be mainly well-tolerated and can promote long-term specific anti-tumor immune responses. Dendritic cells (DCs) as the most potent antigen-presenting cells are vital players in inducing, maintaining and regulating these immune responses and therefore represent a crucial component of vaccination. Considerable objective responses have been achieved with DC-based vaccines. However, this approach alone has not yet met expectations concerning the clinical outcome. Considering this low clinical efficacy, approaches combining therapeutic cancer vaccine strategies with approved agents are being designed. This provides the opportunity to introduce cancer vaccines into treatment at an early point of disease before onset of severe immune exhaustion. However, a critical challenge in using therapeutic agents to promote cancer immunotherapy is that they potentially also influence immune cells in the tumor microenvironment, possibly further impairing their ability to mount immune responses to dying tumor cells. Our group and others have previously demonstrated altered DC phenotype and impaired function by exposure to various therapeutic agents and we focus on elucidating the influence of further therapeutic drugs in order to identify optimal partners for DC-based immunotherapies. Another scientific interest is the role of checkpoint molecules in MM. In contrast to a variety of other cancers, immune checkpoint blockade, e. g. using blocking antibodies to the Programmed cell death protein 1 or its ligand to date has failed to achieve clinical efficacy in MM. Here too, an exhausted immune system may be the reason for missing response. Even though DCs are dominant partners of T cells, the role of DCs in this setting is not well-characterized. Furthermore, other immune checkpoints may be of relevance. One molecule we seek to further analyse in DCs is Osteoactivin, which was recently shown to be an immune checkpoint that impairs T-cell activation. We plan to further elucidate the role of checkpoint molecules in DCs for a possible targeted manipulation of T cell responses in the context of DC-based immunotherapies.
PD Dr. med. Julian Rogasch
Charité – Universitätsmedizin Berlin, Department of Nuclear Medicine
Email: julian.rogasch@charite.de
Fields of Research
- Quantitative Image Parameters
- Non-Small Cell Lung Cancer
- Machine Learning
- Image Biomarkers
Project Title
Machine Learning and Quantitative FDG PET-CT Image Parameters for Diagnostics and Prognosis in Patients with Lung Cancer
Project Description
This project investigates the additional value of machine learning (ML) and quantitative image parameters from FDG-PET/CT in patients with non-small cell lung cancer (NSCLC). In the current clinical application of FDG-PET/ CT, it is usually assessed as an isolated diagnostic tool, and reporting is mostly confined to visual reading. Consequently, the reliability and reproducibility of FDG-PET/ CT reports is variable, which currently entails frequent confirmatory invasive diagnostic procedures. Therefore, substantial advances in the clinical impact of FDG-PET/ CT in improving patient-relevant outcomes may require new paradigms. In this project, ML is used both to derive the image biomarkers and to integrate image data with clinical information, pathology reports and lab results (so-called integrated diagnostics). Different ML methods are investigated, including decision trees as well as deep learning (artificial neural networks). The first application of this methodology is in pretherapeutic thoracic lymph node staging in patients with NSCLC. Retrospective and prospective clinical data are used to develop and validate ML models that provide a differentiated and individualized estimate of the positive and negative predictive value of FDG PET/CT. The goal is to equip clinicians with a decision support system that is ready for clinical use and that allows individualized assessment of the reliability of FDG-PET/CT. This would help physicians to spare more patients additional (confirmatory) invasive staging. The second application that is investigated is the use of ML and quantitative image parameters to predict the patient’s survival after curatively intended treatment. Presently, the treatment decision is mainly determined by the clinical tumor stage although this is not sufficiently differentiated to allow individualized prediction of the patient’s prognosis and the optimal treatment. The current project investigates the additional value of textural features from FDG-PET and CT data to predict the progression-free survival and overall survival in patients with stage I-III NSCLC. These textural features include conventional, mathematically defined features (»radiomics«) as well as classificators derived with deep learning.
Dr. med. Tizian Rosenstock
Charité – Universitätsmedizin Berlin, Department of Neurosurgery
Email: tizian.rosenstock@charite.de
Fields of Research
- Deep neural networks
- Navigated transcranial magnetic stimuation
- Brain tumor surgery
Project Title
Development of Neural Networks for Brain Tumor Patient Imaging Analysis
Project Description
The gold standard for treatment of intrinsic brain tumors is a complete resection since the extent of resection (EOR) is positively correlated with (progression free) survival. However, the goal of complete tumor removal should always be balanced with preservation of function, because eloquent brain tumors imply the risk of a new functional deficits which not only lead to reduced quality of life, but also to reduced survival. We recently validated our risk stratification model based on regression tree analysis that enables to estimate the risk of postoperative motor deficit based on navigated transcranial magnetic stimulation [nTMS] and diffusion tensor imaging (DTI) data. A tumorous motor cortex infiltration and a distance ≤8mm to the corticospinal tract were risk factors for the development of a new postoperative motor deficit. In these cases, the risk was even higher if we could demonstrate impaired cortical excitability, which is determined by the motor resting threshold. The aim of this project is to combine different modalities such as structural MRI scans (with diffusion tensor imaging), nTMS data and patient characteristics using deep neural networks to further increase the accuracy of motor outcome prediction and identify new correlations where appropriate. In our initial analysis, we built on deep neural networks to predict the patients’ postoperative motor status based solely on their preoperative T1 with contrast agent scans. To improve our model performance, we decided to completely revise and adapt the preprocessing of the data and to integrate different modalities in our model as well. After training the model, its performance is further improved by expert validation (supervised learning) and by integrating external data In collaboration with other neurosurgical centers. We plan to develop a freely available web-based decision support tool that can be accessed by any neurosurgeon. In a web-based template, the treating neurosurgeon can enter all relevant patient characteristics and upload the available MRI and nTMS data. The probability of perioperative risk for a new motor deficit is provided, as well as an estimate of the patient's EOR, tumor histology, and survival rate. Relevant risk factors such as tumor motor cortex infiltration or corticospinal tract involvement are reported in a standardized manner.
Dr. med. Lisa-Maria Rosenthal
Charité – Universitätsmedizin Berlin, Department of Congenital Heart Disease, Pediatric Cardiology
Email: lisa‐maria.rosenthal@charite.de
Fields of Research
- Hypoplastic Left Heart Syndrome
- Genetics of Congenital Heart Disease
Project Title
Genetics of Hypoplastic Left Heart Syndrome
Project Description
The Hypoplastic Left Heart Syndrome (HLHS) is a rarecongenital heart defect, where the structures of the left heart and the aortic arch are severely hypoplastic. Without surgical treatment, term infants die within the first days of life. With a three-stage palliative surgical procedure creating a circulatory system with a single ventricle, newborns with HLHS can survive today. Nevertheless, long- term prognosis for patients with HLHS is disappointing, only 50%-70% of newborns survive to age 5 years and survival is associated with significant long-term morbidity. Several observations support a genetic cause for HLHS, as it occurs in children with chromosomal abnormalities and syndromal diseases and seems to have a strong familiar clustering with an increased prevalence of CHD in families with HLHS. The identification of specific genetic variants has been difficult because of the complex inheritance and the low prevalence of HLHS. With new technological and analytical approaches and the establishment of a Family-Screening Programm, where children with HLHS and their relatives are phenotypically and genetically characterized, we hope to identify new genetic variants and recapitulate cardiac maldevelopment of HLHS. We expect that the identification of genetic underpinnings will result in better understanding of HLHS and lead to new approaches in the care of HLHS patients and their families.
Dr. med. Rosa Rößling
Charité – Universitätsmedizin Berlin, Department of Neurology and Experimental Neurology
Email: rosa.roessling@charite.de
Fields of Research
- Autoimmune encephalitis
- Neuronal surface antibodies
- CRISPR Cas technology
Project Title
Identification of New Antibody Targets in Autoimmune Encephalitis
Project Description
Autoimmune encephalitis caused by antibodies targeting neuronal surface antigens is an only recently explored neurological disease that leads to psychiatric and mnestic deficits as well as epileptic seizures and focal neurological signs. New disease-causing antibodies are frequently being detected. Yet in clinical routine, we see many patients with unclear antibody findings, with the pathogenicity being unknown. Precise description of the antigen could not only work as proof of pathogenicity but also justify advanced immunotherapy in patients. It thus represents an immediate medical need. Today detection of an autoantibody using immunohistochemical methods is relatively easy and well established. The exact identification, however, of the antigen targeted by the antibody is still challenging. Even advanced methods using mass spectrometry or phage display fail to identify the complex membrane-expressed native receptor proteins. The proposed project therefore aims at identifying the surface receptors targeted by anti-neuronal autoantibodies by applying a new genome-wide screening method using the CRISPR/Cas9 activation technology. The CRISPR/Cas system is originally known from bacteria where exposition to viral DNA leads to integration in the bacterial genome by inducing double strand-breaks and thus providing a vaccination against future viral invasion. In our project we use a mutated, catalytically inactive (dead) nuclease dCas9 which is still able to bind DNA with high precision. If the dCas9 is led to the promoter region of its target gene by a so-called single guide RNA (sgRNA), it can act as a transcriptional regulator, amplify gene expression, and thereby promote expression of receptor subunits or whole receptors to the cell surface. The use of a genome-wide library of guide RNAs, containing all possible antibody targets, allows for inducing the overproduction of each single antigen in the respective cells. If a patient-derived antibody now binds to one of these cells, we can stain this antibody-labelled cell, sort it by flow cytometry, and select the positive cells. Cells can then be analysed by next-generation sequencing. Identification of the antigens would allow to better judge the autoimmune findings, guide therapeutic options, and facilitate development of target-selective immunotherapy in the future.
PD Dr. med. Anne Rübsam, FEBO
Charité – Universitätsmedizin Berlin, Department of Opthalmology
Email: anne.ruebsam@charite.de
Fields of Research
- Neurodegeneration
- Diabetic Retinopathy
- Oxidative Stress
Project Title
Role and Regulation of Nox4 in Retinal Cells during Diabetes
Project Description
Anti-VEGF therapies have tremendously improved the treatment of proliferative diabetic retinopathy (DR) and macular edema, the two ocular late manifestations of diabetes, but there are still no therapies targeting early stages of the disease to prevent alterations of the neuroretina and thereby preserve visual function. We and others reported on the early neurodegeneration in DR, triggered by pathomechanisms such as inflammation and the ER stress response in retinal neurons and Müller glial cells (MGCs) subjected to diabetes-related metabolic stress conditions and in streptozotocin (STZ) – induced diabetic mice. Numerous reports indicate the importance of oxidative stress in the development of the early neurodegenerative changes in DR. Hyperglycemia-dependent generation of reactive metabolites lead to excessive reactive oxygen species production (ROS), which are likely to be a key contributor to the development of DR. NADPH (Nox) enzymes generate reactive oxygen species (ROS) and they are widely distributed throughout the retina. Compelling evidence suggests, that in particular Nox4 is an important source of ROS in the retina during DR and thus contributes to the vascular pathology in DR. Still today, there is a gap of knowledge regarding the role and regulation of Nox4 in cell types other than vascular cells, namely retinal neurons, MGCs, and pericytes. Thus with this proposed research project, I aim to develop a complete picture of Nox4 activity in the retina during diabetes by evaluating the role and regulation of Nox4 as a major source of ROS in the aforementioned cells under diabetic conditions in vitro and in two models of diabetes (type 1 & 2) in vivo. We further want to evaluate the rationale of Nox4 inhibition in preventing oxidative stress-induced early neurodegenerative changes in DR. If such a treatment could be realized, it may be possible to arrest DR at the earliest stages of its development.
Dr. med. Julia Sbierski-Kind
PD Dr. med. Thomas Schachtner
Charité – Universitätsmedizin Berlin, Medical Department, Division of Nephrology and Internal Intensive Care Medicine
Email: thomas.schachtner@charite.de
Fields of Research
- Transplant Medicine
- Transplant Immunology
- Immunology of Infection
Project Title
Adoptive T-Cell Therapy with Enrichment of Central Memory T-Cells in Solid Organ Transplant Recipients with CMV Infection Resistant to Antiviral Therapy
Project Description
We demonstrated feasibility, efficacy, and safety of adoptive T-cell therapy with CMV-specific cytotoxic T-cells (CMV-CTL) in solid organ transplant recipients with CMV disease. Adoptive T-cell therapy, however, showed not to be long-lasting. We hypothesize that our 2nd generation CMV-specific CTL product enriched for central memory T-cells (TCM) by partial blocking of IL-2R signaling is more long-lasting and effective than our 1st generation product enriched for effector memory T-cells (TEM). This hypothesis will be measured by the ability of these 2 preparations to augment the impaired CMV immune function and decrease high CMV-loads in immunocompromised solid organ transplant with repeated or persistent active CMV-infection resistant to antiviral therapy. CMV seropositive patients will be randomly allocated to two study arms: Arm A: TEM-enriched autologous CMV-CTL product (low proportion of TCM and high numbers of antigen-specific, induced regulatory T-cells). Arm B: TCM-enriched autologous CMV-CTL product (generated in the presence of partial IL-2R inhibition with enrichment of CD4+/CD8+ TCM-like cells). Here, we aim to: (1) start a clinical trial to prove the hypothesis of prolonged efficacy of TCM-enriched autologous CMV-CTL, (2) follow the fate of our adoptively transferred T-cells by monitoring the TCR-repertoire by next-generation sequencing (NGS), (3) understand the mechanisms stabilizing the phenotype of TCM, and (4) extend our studies to other viruses.
Dr. med. Marie Schafstedde
Charité – Universitätsmedizin Berlin, Institute of Computer-assisted Cardiovascular Medicine and German Heart Center Berlin, Congenital Heart Defects - Pediatric Cardiology
Email: schafstedde@dhzb.de
Fields of Research
- Image Based Numerical Modelling
- Machine Learning
- Digital Health
Project Title
Hybrid Modelling: Combining Machine Learning with Physiology Based Models in Cardiovascular Medicine
Project Description
With increasing affordability of computational power as well as improvements in medical imaging technology, image-based numerical modelling of hemodynamics is gaining increased attention within the medical community. Apart from improving our understanding of the cardiovascular system through in-silico studies, such methods hold the potential to substantially improve treatment decision and outcome prediction capabilities. Using patient-specific 3-dimensional image data combined with computational fluid dynamics (CFD) solver, the ability to non-invasively predict treatment-critical hemodynamic parameters has been demonstrated. However, such methods are time consuming, cost-intensive and require substantial user interaction. As an alternative to CFD, we propose a novel machine-learning (ML) based method that is user friendly and produces results almost instantly. The challenge herein lies in providing a sufficient amount of training data for ML-based methods. Such an amount is not found even in large multicenter studies. To overcome this data gap, available patient-specific data is augmented using a statistical shape model (SSM). With this hybrid approach, we aim to overcome the aforementioned limitations of traditional numerical techniques and to improve clinical feasibility of patientspecific in-silico modelling, thereby facilitating clinical translation. As a proof of concept, this project develops an ML-based non invasive diagnosis method for patients with aortic stenosis, one of the most common acquired cardiovascular diseases.
PD Dr. med. Michael Scheel
Charité – Universitätsmedizin Berlin, Department of Radiology (including Pediatric Radiology)
Email: michael.scheel@charite.de
Fields of Research
- Neuroimaging/Diffusion Tensor Imaging
- Neurodegenerative Diseases
- Neuroinflammatory Diseases
Project Title
Diffusion Tensor Imaging – New Possibilities in Diagnostic Radiology
Project Description
Diffusion Tensor Imaging (DTI) allows a non-invasive diffusion-based tissue characterization and thus offers completely new possibilities in the field of diagnostic radiology. On the one hand, this method allows an improved detection of pathological changes at the microstructural level, which are frequently not detectable in conventional MRI methods. On the other hand, new strategies for therapy monitoring are feasible by quantification of diffusion parameters (e.g., Parallel, Radial and Mean Diffusivity and Fractional Anisotropy - PD, RD, MD, FA). We evaluated DTI in different neuropsychiatric diseases (e.g. amyotrophic lateral sclerosis, schizophrenia, anti-NMDA receptor encephalitis) and investigated if DTI can detect pathological changes, even if the standard imaging remains normal. In amyotrophic lateral sclerosis, we could demonstrate the reliable detection of microstructural changes in the corticospinal tract. We also identified the main factors that influence diagnostic accuracy using different DTI evaluation strategies. The results reveal how sensitivity and specificity values can be optimized to a level that makes an imaging-based ALS diagnosis possible. Routine MR imaging in patients with schizophrenia is usually also unremarkable. DTI studies in the past have demonstrated an affection of fro-no temporal fiber tracts reflected by a decrease of FA values. We were able to demonstrate that the reduction of FA values within the frontotemporal white matter is based on an increase in radial diffusivity, which suggests an impaired myelination of fiber tracts. Similarly, in patients with anti-NMDA receptor encephalitis, we could demonstrate that despite unremarkable standard imaging extensive structural ab- normalities exists, particularly in the cingulate fiber tracts. For the first time, our study provided a neurobiological explanation for the neuropsychological cognitive deficits in this patient group. DTI opens up new possibilities and applications in the field of diagnostic radiology. However further optimization and standardization with respect to imaging protocols and evaluation methods are needed. If this succeeds, DTI will soon belong to the essential methods in diagnostic radiology.
PD Dr. med. Jan Friedrich Scheitz
Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology
Email: jan‐friedrich.scheitz@charite.de
Fields of Research
- Ischemic Stroke
- Thrombolysis in Ischemic Stroke
- Cardiac Complications After Stroke
Project Title
Predictors of Acute Complications After Acute Ischemic Stroke
Project Description
Prognosis of ischemic stroke is highly dependent on the occurrence of complications during the acute phase. The aim of the research project is to identify predictors of acute complications after acute ischemic stroke in order to improve treatment and outcome of patients. The project will focus on two major aspects A) Underlying causes and prognostic relevance of myocardial injury (elevation of cardiac troponin) after stroke and B) Secondary hemorrhagic complications and functional outcome in ischemic stroke patients treated with thrombolysis. A) Cardiac troponin is a sensitive biomarker for myocardial injury. Interpretation of elevated troponin levels in the setting of acute ischemic stroke is a clinical challenge. Elevated troponin may signify coincident acute coronary syndrome, but may also occur secondary to CNS-injury. Currently, there is only a little evidence regarding the optimal care of stroke patients with elevated troponin. Therefore, the aim of the project is to elucidate the underlying causes of myocardial injury after stroke. This relevant because troponin elevation is frequently observed after stroke and strongly associated with mortality. B) Thrombolysis with the recombinant tissue-plasminogen activator is an evidence-based treatment for acute ischemic stroke. Symptomatic intracerebral hemorrhage (sICH) following thrombolytic treatment is the most feared complication and occurs in 2-9% of patients. The occurrence of sICH is associated with a high mortality and poor functional recovery. The aim of the project is to identify predictors of sICH in order to counsel patients about their individual risk and to improve the care of high-risk patients.
Dr. med. Anja Schirbel
Dr. med. Ludwig Schlemm
Charité – Universitätsmedizin Berlin , Department of Neurology with Experimental Neurology
Email: ludwig.schlemm@charite.de
Fields of Research
- Health Services Research
- Decision‐Support Algorithms
- Acute Ischemic Stroke Care
Project Title
Personalized Management of Acute Ischemic Stroke Patients
Project Description
Patients with acute ischemic stroke due to proximal large vessel occlusion should undergo timely mechanical thrombectomy in addition to intravenous thrombolysis. The prehospital setting, the optimal transport strategy for acute ischemic stroke patients with unknown vessel status is uncertain whenever transport time to the nearest non-mechanical thrombectomy-capable primary stroke center is shorter than to the nearest mechanical thrombectomy-capable comprehensive stroke center. Under these circumstances, initial transportation to the primary stroke center would be associated with shorter delays to thrombolysis. However, if the primary stroke center does not provide endovascular treatment, patients with proximal vessel occlusion require a secondary transfer that results in longer delays to mechanical thrombectomy. Direct transportation to the nearest comprehensive stroke center, on the other hand, would lead to quicker access to mechanical thrombectomy for patients with proximal vessel occlusion but possibly longer onset-to-thrombolysis times. How to determine the optimal transport destination for any given patient is unclear. We propose that the decision about the most adequate transport destination for acute ischemic stroke patients in the prehospital acute setting should be based on predicted clinical outcomes associated with the available transport destination options (nearest comprehensive or primary stroke center). The most relevant predictors of good outcome that are obtainable in the prehospital setting are age, sex, and stroke symptom severity. In addition, for each transport destination, potential time from symptom onset-to-needle, time from symptom onset-to-groin puncture, and time from needle-to-groin puncture can be estimated based on geographic data, available means of transport, and historical performance metrics of each stroke center. Importantly, the presence (or absence) of a proximal vessel occlusion is not known but can only be estimated based on clinical parameters. Using novel mathematical prediction models and data from prospective multi- centric registers, we will examine the usefulness of clinical decision-support algorithms to individualize prehospital triage decisions for patients with suspected acute ischemic stroke and unknown vessel status. The project’s goal is to improve clinical outcome for patients with acute ischemic stroke by ensuring wide-spread and timely access to the most adequate reperfusion therapy within different health care settings.
PD Dr. med. Ludwig Schlemm
Charité – Universitätsmedizin Berlin , Department of Neurology with Experimental Neurology
Email: ludwig.schlemm@charite.de
Fields of Research
- Health Services Research
- Decision‐Support Algorithms
- Acute Ischemic Stroke Care
Project Title
Personalized Management of Acute Ischemic Stroke Patients
Project Description
Patients with acute ischemic stroke due to proximal large vessel occlusion should undergo timely mechanical thrombectomy in addition to intravenous thrombolysis. The prehospital setting, the optimal transport strategy for acute ischemic stroke patients with unknown vessel status is uncertain whenever transport time to the nearest non-mechanical thrombectomy-capable primary stroke center is shorter than to the nearest mechanical thrombectomy-capable comprehensive stroke center. Under these circumstances, initial transportation to the primary stroke center would be associated with shorter delays to thrombolysis. However, if the primary stroke center does not provide endovascular treatment, patients with proximal vessel occlusion require a secondary transfer that results in longer delays to mechanical thrombectomy. Direct transportation to the nearest comprehensive stroke center, on the other hand, would lead to quicker access to mechanical thrombectomy for patients with proximal vessel occlusion but possibly longer onset-to-thrombolysis times. How to determine the optimal transport destination for any given patient is unclear. We propose that the decision about the most adequate transport destination for acute ischemic stroke patients in the prehospital acute setting should be based on predicted clinical outcomes associated with the available transport destination options (nearest comprehensive or primary stroke center). The most relevant predictors of good outcome that are obtainable in the prehospital setting are age, sex, and stroke symptom severity. In addition, for each transport destination, potential time from symptom onset-to-needle, time from symptom onset-to-groin puncture, and time from needle-to-groin puncture can be estimated based on geographic data, available means of transport, and historical performance metrics of each stroke center. Importantly, the presence (or absence) of a proximal vessel occlusion is not known but can only be estimated based on clinical parameters. Using novel mathematical prediction models and data from prospective multi- centric registers, we will examine the usefulness of clinical decision-support algorithms to individualize prehospital triage decisions for patients with suspected acute ischemic stroke and unknown vessel status. The project’s goal is to improve clinical outcome for patients with acute ischemic stroke by ensuring wide-spread and timely access to the most adequate reperfusion therapy within different health care settings.
PD Dr. med. Frieder Schlunk
Dr. med. Katharina Schmack
Charité – Universitätsmedizin Berlin, Department of Psychiatry and Psychotherapy
Email: katharina.schmack@charite.de
Fields of Research
- Psychosis
- Visual Perception
- Computational Psychiatry
Project Title
The Neurobiology of Delusions – Linking Perceptual Inference and Dopamine
Project Description
Delusions are a core symptom of psychotic diseases such as schizophrenia. They refer to beliefs that are not supported by evidence but are nonetheless held with strong conviction. Delusions can cause great suffering to the affected persons and their environment. For instance, affected persons frequently experience intense fear because they feel persecuted and observed, although outside observers cannot find any indication of such a threat. There is convincing scientific evidence that delusions are associated with excessive signaling of the neurotransmitter dopamine, but it is not well understood how such an excess in dopamine signaling might lead to the formation of delusions. Influential theories postulate alterations in the brain’s inferencing machinery that controls perception, such that expected and insignificant stimuli are automatically perceived as surprising and significant and the cognitive effort to make sense out of such aberrant salience results in the formation of delusions. However, the role of dopamine in such perceptual inference has remained unclear. Therefore, the current project is aimed at establishing an empirical link between dopamine, perceptual inference, and delusions. To this end, we will conduct behavioral and functional imaging experiments in individuals with schizophrenia and healthy participants. By the use of mathematical models, we will then the mechanisms underlying perceptual inference. We will test whether these inferential mechanisms are altered in delusions or can be influenced by drugs that stimulate or inhibit dopamine signaling in the brain. If successful, this project will contribute to an understanding of the role of dopamine in perceptual processes that are compromised in delusions.
Dr. med. Laura Katharina Schmalbrock
Charité – Universitätsmedizin Berlin, Department of Hematology, Oncology and Cancer Immunology
Email: laura.schmalbrock@charite.de
Fields of Research
- Acute myeloid leukemia
- Multiple Myeloma
- Drug resistance
Project Title
Functional Characterization of Genomic Networks in Acute Myeloid Leukemia Using CRISPRi/a Screenings
Project Description
While large sequencing studies have comprehensively characterized recurrent gene mutations in acute myeloid leukemia (AML), the functional consequences of these mutations and the impact of genetic interactions that drive leukemogenesis are less well understood. Mutations in epigenetic modifying genes, such as Isocitrate dehydrogenase 1 and 2 (IDH1/2) and Additional sex combs like 1 (ASXL1), occur frequently in AML patients. It is known that these mutations alter methylation status, which affects cell differentiation and gene expression. In mouse models however, these mutations alone did not induce leukemia, pointing to additional genetic alterations that play a role in leukemogenesis. Genome wide CRISPR screens are powerful tools to identify and functionally characterize genes and vulnerabilities in cancer. In addition to CRISPR-Cas9 knock-out screenings, which are commonly used in most studies, more recently gain- and loss-of-function CRISPRa/CRISPRi screenings have been developed, which enable to comprehensively study activation and inhibition of gene expression. Within my project, we plan to perform genome wide CRISPR activation (CRISPRa) and CRISPR interference (CRISPRi) screenings to identify novel genes and pathways that promote leukemogenesis with focus on mutations in epigenetic regulating genes (IDH1, ASXL1). Besides a deeper understanding of the genomic network that promotes leukemogenesis in the context of these specific mutations, we eventually aim at finding new vulnerabilities that can be used for pharmacological targeting, thus translating our findings into the clinic.
PD Dr. med. Felix Alexander Schmidt
Charité – Universitätsmedizin Berlin , Department of Neurology with Experimental Neurology
Fields of Research
- Multiple Sclerosis and Neuromyelitis Optica
- Afferent Visual and Olfactory System
- Imaging
Project Title
B-Mode Ultrasound as a Novel Non-Invasive Quantitative Imaging Biomarker for the Functional Assessment of the Afferent Visual Pathway
Project Description
This project addresses the clinical need of quantifying objectively a relative afferent pupillary defect (RAPD), the pathognomonic clinical sign of optic nerve damage due to optic neuritis (ON). The ultimate goal of this project is to establish ultrasound as a novel non-invasive objective imaging biomarker for the functional and quantitative assessment of afferent visual pathway damage. ON is a common symptom of demyelinating CNS conditions such as multiple sclerosis and neuromyelitis spectrum disorder, leading to severe visual impairment and reduced vision-related quality of life. Early detection and quantification of ON are essential for treatment decisions to improve clinical outcome. Of note, objective quantification of RAPD may also have implications for clinical trials with visual endpoints. Future trials could benefit from a reliable and reproducible RAPD evaluation method such as the B-mode ultrasound approach. In a recent study we performed the first systematic evaluation of B-mode ultrasound for assessment of the pupillary light reflex (PLR) and provided normal values for ultrasound derived PLR parameters for 100 subjects in 4 different age groups (Schmidt et al. PlosOne 2017). PLR assessment with ultrasound in our study was well tolerated, rapidly acquired and had a good test-retest reliability. The goals of this research project are to directly compare the ocular ultrasound approach with infrared video pupillometry for RAPD assessment and to compare B-mode ultrasound with visual evoked potentials and optical coherence tomography, two established methods that measure subclinical damage of the optic nerve. In a longitudinal study, we want to establish the value of B-mode ultrasound for monitoring disease activity and for outcome prediction in patients with ON. As the PLR is influenced by the autonomous nerve system, we also want to collect PLR data from neurological patients with known autonomous nerve dysfunction such as patients with multiple system atrophy.
Dr. med. Maren Schmiester
Charité – Universitätsmedizin Berlin, Department of Hematology, Oncology and Cancer Immunology
Email: maren.schmiester@charite.de
Fields of Research
- Lymphoma
- Host-Microbiota Interactions
- Flow Cytometry
Project Title
Analysis of the Interdependence Between the Intestinal Microbiota, Lymphoma Disease and Therapeutic Immunochemotherapy
Project Description
Constant crosstalk between immune cells and the intestinal microbiota at the level of the gut allows for a symbiotic tolerance, modulates local immunity and impacts innate and adaptive immune response. While the immune system has long been recognized as a major factor in cancer control, there is recent mounting evidence supporting the influence of the microbiota on both carcinogenesis and on the response to immunochemotherapy across various forms of malignant disease. Vice versa, immunochemotherapy is known to disrupt microbial homeostasis and thereby contribute to therapy-related complications such as bloodstream infections. Malignant lymphoma is innately linked to the immune system: it arises from lymphoid cells and its progression is characterized by numerous mechanisms of immune escape. The close physical contact of circulating lymphoid cells and the microbiota within the intestinal immune system and their bidirectional relationship is highly suggestive of a complex and thus far insufficiently examined interdependence. We plan to address the possible link between lymphoma disease and the intestinal microbiota by analysing the microbial composition of healthy subjects and lymphoma patients at the point of diagnosis and longitudinally during immunochemotherapy. To do so, we will establish a flow cytometric-based approach for human samples, perform segregated analyses of cell abundances in microbial subcommunities and examine their dynamic changes. To validate our findings, we will also employ the gold standard for microbiota profiling, 16s ribosomal DNA sequencing. The analyses are embedded in a comprehensive immune monitoring algorithm, allowing us to integrate various patient and tumor parameters. Correlations with clinical and laboratory parameters (e.g. incidence, duration and type of infections, treatment response, blood counts) will be performed to determine the impact of the microbiota on the clinical outcome of lymphoma patients.
Dr. med. Rosa Bianca Schmuck
Charité – Universitätsmedizin Berlin, Department of Surgery
Email: rosa.schmuck@charite.de
Fields of Research
- Cancer Stem Cells
- Tumor Associated Stromal Cells
- Pancreatic Cancer
Project Title
Cancer Stem Cells and Tumor-Associated Stromal Cells in Pancreatic Cancer
Project Description
Pancreatobiliary carcinomas demonstrate an unfavorable prognosis and a poor response to chemotherapy. Cancer stem cells (CSCs) may define the malignant potential of a neoplasm through tumor initiation and chemotherapy resistance. The aim of the project is the genotypic, phenotypic and functional characterization of the tumor stem cell fraction in pancreato biliary malignoms. Special focus is set on the Notch-signaling pathway as a potential therapeutic target. The hypothesis is then to be evaluated in vitro, in vivo and in a representative cohort of patients with pancreato biliary malignoms. The main focus will be the analysis of patient-derived tumor cell lines and co-culture with tumor-associated stromal cells as better treatment options require a fundamental understanding of the tumor’s microenvironment and the complex interaction between tumor and other cell types, especially stromal cells. Furthermore, the question to what extend tumor-associated stromal cells hold a genuine malignant potential or whether those cells act as benign bystander cells remains unanswered. Therefore, the interaction between CAFs and cancer cells is going to be studied in a novel approach by measuring the cell viability of tumor components (cancer cells and CAFs) in direct and indirect co-cultures.
Dr. med. Joanna Barbara Schneider
Charité – Universitätsmedizin Berlin, Division of Neuropediatrics
Email: joanna.schneider@charite.de
Fields of Research
- Muscle Stem Cells (Satellite Cells)
- Epigenetic Changes
- Critical illness Myopathy
Project Title
Epigenetic Changes and Repair of the DNA Breaks in Skeletal Muscle in Critical illness Myopathy
Project Description
Critical illness myopathy (CIM) is a devastating acquired skeletal muscle disease characterized by atrophy, flaccid paralysis and respiratory failure. It develops in very ill patients during the course of critical illness and is a frequent complication of intensive care unit (ICU)-treatment. It is a very peculiar aspect of CIM that skeletal muscle atrophy and weakness last for a prolonged period of time, often life-long, although all identified risk factors like inflammation, hyperglycemia, medications etc. have been removed. We hypothesize that the acute onset of severe critical illness with its dramatic hormonal, metabolic and nutritional disturbances leads to epigenetic changes in skeletal muscle stem cells or early myoblast. The epigenetic changes lead to an impaired ability of the muscle to regenerate and a long-lasting myopathy associated with critical illness that typically extends far beyond the duration of the ICU stay. Furthermore, the epigenetic changes lead to an increase of DNA double breaks in the muscle cells. This project aims to identify and characterize the epigenetic modifications in muscle stem cells derived from severely ill patients within the first days after admission to the ICU. We analyze the epigenome and transcriptome as well as the DNA double-breaks process of activated satellite cells and early myoblasts derived from acute onset CIM patients.
Felix Thomas Schoknecht
Charité - Universitätsmedizin Berlin, CC 15 - Klinik für Neurochirurgie mit Arbeitsbereich pädiatrische Neurochirurgie (CCM)
Email: felix-thomas.schoknecht@charite.de
Fields of Research
- Subarachnoid Hemorrhage (SAH)
- 19F Magnetic Resonance Imaging
- Inflammation
Project Title
19F Magnetic Resonance Imaging in Experimental Subarachnoid Hemorrhage
Project Description
Subarachnoid hemorrhage (SAH) caused by rupture of an intracranial aneurysm leads to bleeding in the subarachnoid space (SAS), and is a devastating disease associated with significant morbidity and mortality. Secondary brain injury and associated inflammatory events following SAH arise as a major contributor to the patient’s poor clinical outcome. Previous evidence has shown that nanoemulsions prepared from perfluoro-5-crown-15-ether (PFCE) preferably label inflammatory cells, clearing the nanoparticles from circulation by phagocytosis. The advantageous lack of 19F background signal enables specific in vivo detection of inflammatory foci by 19F MRI via immunocompetent PFCE-loaded cells. In this project, we aim to visualize and track the patterns of immune cell activation following SAH using PFCE.
A filament perforation surgery is performed to induce SAH in C57BL/6 mice, and Sham operation is done for the matching control groups. Following the surgery, mice receive an intravenous injection of the PFCE nanoemulsion. Accumulation of 19F particles is visualized at different time points in vivo by 1H/19F 7T magnetic resonance imaging. Immunofluorescence staining for nuclei, arachnoid cells, microglia, macrophages and neutrophil granulocytes is performed to elucidate the histological location of PFCEs using their rhodamine labelling. Afterwards, brain parenchyma and SAS are analyzed using confocal microscopy and FACS.
The data collected so far indicate that, PFCE nanoemulsions generate positive 19F MRI contrast for the discrimination between subarachnoid hemorrhage and Sham operation, as well as imaging of SAH-associated inflammation in the hypothalamus, basal brain parenchyma and SAS directly bordering the perforated vessel via magnetic resonance, making use of matching anatomic 1H and highly specific 19F images. Moreover, the detection of leptomeningeal PFCEs might give further insights into the lymphatic drainage of the subarachnoid space and central nervous system following SAH. Utilizing nontoxic PFCEs may enable monitoring of the immune cell activation and blood clearance after subarachnoid hemorrhage and therefore, serve as a modality to monitor therapeutic response in further translational treatment studies in SAH.Dr. med. Stefanie Schreiter
Charité – Universitätsmedizin Berlin, Department of Psychiatry and Psychotherapy
Email: stefanie.schreiter@charite.de
Fields of Research
- Schizophrenia
- Pharmacogenetics and ‐epigenetics
- Functional Neuroimaging
Project Title
Phenomics and Genomics of Clozapine Pharmacotherapy
Project Description
Clozapine is generally prescribed if at least two trials of antipsychotic agents have not led to satisfactory clinical improvement, thereby implying that patients on Clozapine generally suffer from more severe and/or persistent symptoms than patients suffering from schizophrenia spectrum disorders (SCZ) on other antipsychotic agents. Unraveling the (functional) genetic variation underlying this severe SCZ phenotype, therefore, has the potential to deepen our understanding of the biological underpinnings of SCZ beyond the boundaries of DSM-based consensus criteria. We here hypothesize that targeting this phenotype in genome-wide association studies and next-generation sequencing studies will signal genetic risk loci implicated in this severe SCZ phenotype. In the future, this may lead to early detection of severe SCZ, which in turn will enable tailoring of pharmacotherapeutic strategies to such SCZ sub-types. Though Clozapine is one of the most effective antipsychotic medications, it goes along with life-threatening adverse drug reactions, such as agranulocytosis, diabetic ketoacidosis, metabolic syndrome or obsessive-compulsive symptoms. Prescribing Clozapine in clinical practice, therefore, requires balancing adverse reactions risk profile likelihoods with clinical response probabilities. This need highly contrasts with the current state of knowledge as it is unknown who will respond to Clozapine and to what degree a specific patient may develop side effects. Based on preclinical studies, we hypothesize that epigenetic and gene expression mechanisms influence treatment outcome after CLZ initiation. We will, therefore, investigate methylation patterns/levels and gene expression profiles before and after initiation of CLZ pharmacotherapy. Furthermore, we will try and identify other predictive factors for treatment outcome following CLZ pharmacotherapy initiation. The overarching goal is to create a prediction model for clozapine response. This model includes genetic, epigenetic and clinical data.
PD Dr. med. Vera Schreiter
Charité – Universitätsmedizin Berlin, Department of Radiology (including Pediatric Radiology)
Email: vera.schreiter@charite.de
Project Title
PSMA Theranostic of Prostate Cancer: Radionuclide Therapy and Functional Molecular Hybrid Imaging by MRI and PET
Project Description
The aim of this project is to develop new strategies for personalized theranostic management of prostate cancer by using prostate-specific membrane antigen (PSMA). PSMA is a transmembrane protein which can serve as a specific target structure for hybrid imaging of prostate cancer with the new tracer Ga-68 HBED-CC PSMA as well as for new treatments of prostate cancer such as radionuclide therapy using lutetium-177. This project deals with the evaluation of parameter specification such as biodistribution and biokinetics of the new tracer Ga-68 HBED-CC PSMA for imaging prostate cancer. Further, the potential of multimodal functional molecular hybrid imaging such as PET/CT and PET/MRI of prostate cancer and effects on personalized medicine are investigated. New therapeutic strategies in radionuclide therapy of prostate cancer with lutetium-177 are evaluated focusing on the use of radiosynthesizers and radioprotectors to enable higher therapeutic doses of lutetium-177 to be delivered for the treatment of prostate cancer.
Dr. med. Eva Vanessa Schrezenmeier
Charité – Universitätsmedizin Berlin, Medical Department, Division of Nephrology and Internal Intensive Care Medicine
Email: eva‐vanessa.schrezenmeier@charite.de
Fields of Research
- Acute Kidney Injury
Project Title
Identification of Biomarkers for Acute Kidney Injury
Project Description
Acute kidney injury is a common and potentially life-threatening condition. At the moment the diagnosis of AKI is made by a rise in serum creatinine. The serum creatinine level acts as a measure of the glomerular filtration rate. When the glomerular filtration rate decreases in case of AKI it can take up to 48 hours before an increase in se- rum creatinine is detectable. This leads to a delayed diagnosis of kidney injury. Some new biomarkers e.g. neutrophil gelatinase-associated lipocalin (NGAL) can detect kidney injury already two hours after the causing event. However, these new markers, as well as serum creatinine, stay elevated for several days after the causing event. The expression profiles of these new biomarkers allow the detection of AKI in an early phase but not the assignment to a time phase of AKI. We were able to show in a mouse model of ischemia-reperfusion that cation trans- port regulator homolog 1 (Chac1) is transcriptionally induced in an early phase of AKI. The expression is very short-range and already 48h after the causing event the mRNA levels of Chac1 has normalized to baseline. This is in contrast to the intrarenal mRNA level of NGAL and serum creatinine, which are elevated in all phases. With- in the junior CSP, the results on Chac1 could be validated in a preliminary study of human AKI. ELISA development for this new biomarker for larger proof-of-concept studies is on its way.
PD Dr. med. Eva Vanessa Schrezenmeier
Charité – Universitätsmedizin Berlin, Medical Department, Division of Nephrology and Internal Intensive Care Medicine
Email: eva‐vanessa.schrezenmeier@charite.de
Fields of Research
- Immunology
- Nephrology
- Vaccine response
Project Title
Epigenetic Regulation of Plasma Cell Differentiation in Systemic Lupus Erythematosus
Project Description
B cell-directed therapies have improved prognosis for some autoimmune kidney diseases like PLA2R+ membranous glomerulonephritis and minimal change disease. However, other diseases like SLE are refractory to B cell-depletion and even plasma cells-directed therapy may not work for alloantibody production in kidney transplant patients. In Nephrology, we can study various ways of B and plasma cell induction and maintenance, from transient B cell-autoimmunity to persistent auto/alloimmunity
mediated by plasma cells. Current immunosuppressive therapies are unselective, make patients
vulnerable to severe infections and impair proper vaccine response. Therefore, selective and potent targeting of auto/alloreactive B and plasma cells remains an important medical need. I hypothesize that B cell and plasma cell induction, differentiation and maintenance is distinct between persistent and transient auto/alloimmunity leading to kidney diseases and that different strategies are needed to successfully treat different auto/alloantibody mediated kidney diseases.Dr. med. Stefanie Schulte
Charité – Universitätsmedizin Berlin, Department of Pediatrics, Division of Oncology and Hematology
Email: stefanie.schulte@charite.de
Fields of Research
- MicroRNAs in Tumor Biology
- Targeted Cancer Therapy/Survivin
- Neuroblastoma
Project Title
Targeting Survivin in Neuroblastoma
Project Description
Neuroblastoma is the most common extracranial solid tumor of childhood, accounting for approximately 20% of all childhood cancer deaths. The relapse rate of high-risk neuroblastoma exceeds >50% despite most intensive multimodal treatment, and relapsed neuroblastoma is almost always fatal. Therefore, new treatment strategies for high-risk neuroblastoma are an urgent, but still unmet medical need. The most common genomic alterations in high-risk neuroblastoma comprise amplification of the MYCN oncogene (in approx. 40% of all cases) and gain of chromosome 17q (in >60% of all cases). The oncogene BIRC5 (en-coding the protein Survivin) is located on chromosome 17q, upregulated by MYCN, and was found to be strongly overexpressed in high-risk neuroblastoma. Survivin is involved in suppression of apoptosis, mitosis, cell cycle, metabolism, invasion and several other key cellular functions. Knock-down of Survivin in neuroblastoma cell lines resulted in cell death. Treatment of neuroblastoma cell lines or mice with neuroblastoma xenografts with the Survivin inhibitor YM- 155 resulted in cell death and tumor regression. However, more recent studies revealed YM-155 treatment to result in unspecific DNA damage and other unspecific effects rather than specific inhibition of Survivin. In the current project we (a) analyze the contribution of Survivin to neuroblastoma pathogenesis and metastasis, (b) assess the specific functions of Survivin in neuroblastoma, and (c) model specific strategies to inhibit Survivin.
Dr. med. Wibke Schulte
Charité – Universitätsmedizin Berlin, Department of Surgery
Email: wibke.schulte@charite.de
Fields of Research
- Macrophage Migration Inhibitory Factor
- Sepsis
- Emergency General Surgery
Project Title
Role of MIF in Human Acute Peritonitis
Project Description
Sepsis, defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, is a leading cause of death in intensive care units worldwide. Management of sepsis includes timely control of the infection source, which in sepsis resulting from intraabdominal infection often requires emergent surgery. Delay of surgical intervention and inability to obtain source control dramatically increase mortality. However, it remains controversial whether source control should be followed by complete reconstruction of the gastrointestinal tract during emergent surgery or whether limited and repeated surgical interventions according to a damage control strategy pose additional benefit. Macrophage migration inhibitory factor (MIF) is an immunoregulatory cytokine that is of special interest in sepsis pathophysiology because functional MIF polymorphisms predict mortality in different infections, and experimental studies indicate that anti-MIF improves survival even when administered eight hours after infectious insult. Our preclinical data indicate that MIF levels are elevated in septic shock, that MIF recruits highly proinflammatory macrophage subsets to the site of peritoneal infection and that MIF regulates macrophage activation responses that mediate lethal septic shock, thus suggesting avenues for new therapeutic approaches to sepsis. We hypothesize that the severity of peritoneal infection and the precise nature of intraabdominal inflammation with respect to macrophage activation determine the success of surgical reconstruction in the acute setting. Our preclinical data indicate that MIF substantially aggravates sepsis disease progression and suggest that pharmacologic inhibition of MIF may be of therapeutic value. To further define mechanisms that control favorable surgical results and, thus, sepsis outcome we propose two specific aims: 1. To precisely characterize macrophage responses in human acute peritoneal infection/ inflammation, and 2. To establish mechanisms by which MIF aggravates human disease progression, and to test the value of pharmacological MIF inhibition as a potential therapeutic target to diminish sepsis-related mortality.
Dr. med. Emanuel Schulz
Charité – Universitätsmedizin Berlin, Medical Department, Division of Gastroenterology, Infectiology and Rheumatology
Email: emanuel.schulz@charite.de
Fields of Research
- Epithelial Barrier
- Intestinal Pathogens
- Gastrointestinal Inflammation
Project Title
Epithelial Polarity and Intestinal Inflammation
Project Description
Phosphatidylinositol phosphates (PtdInsP) sum up for just a small percentage of the lipids in the plasma membrane in epithelial cells. Yet, as a source important second messengers they are key substrates in multiple membrane functions, e.g. endocytosis, exocytosis, enzyme activation and actin skeleton organization, to name but a few. Their asymmetric distribution on the inner leaflet of the plasma membrane is crucial for cell homeostasis and differentiation. An essential enzyme in the PtdInsP metabolism is Phosphatase and Tensin homolog (PTEN). It dephosphorylates PtdIns(3,4,5)P3, thereby suppressing Akt/PKB activation. PTEN localizes in the apical membrane during epithelial morphogenesis and polarization and leads to apical enrichment of PtdIns(4,5)P2. In our study, we developed a transfection model of intestinal Caco2 cells with a GFP-linked PtdIns(4,5)P2-binding domain (PLC-delta- PH-GFP). Thereby we are able to display the PtdIns(4,5) P2- distribution among the cells with a focal laser scanning microscope. Using life cell imaging technique, changes in PtdIns(4,5)P2-distribution could be observed in the course of cell infection with bacterial pathogens. In a screening with various intestinal pathogens, we identified an Escherichia coli exotoxin that induces a delocalization of the PtdIns(4,5)P2-signal from the plasma membrane. Barrier analyses on confluent polarized PLC-delta-PH-GFP-transfected Caco2-monolayers revealed simultaneously occurring barrier defects of the epithelium. Our goal is to gain further insight into the underlying mechanisms and de- pict the cellular structures which are involved in the toxin-induced perturbation of the epithelial barrier.
PD Dr. med. Michael Schumann
PD Dr. med. Leonille Schweizer
Charité – Universitätsmedizin Berlin, Department of Neuropathology
Email: leonille.schweizer@charite.de
Fields of Research
- Cancer Genetics
- Epigenetics
Project Title
Molecular Characterization of Spinal Paragangliomas
Project Description
Paragangliomas are rare neuroendocrine neoplasms that can develop at various body sites including the head, neck, thorax, and abdomen. Approximately 25% have an unfavorable course and patients with metastatic paragangliomas have limited treatment options and poor prognosis. Unlike other types of cancer, there is no established grading system and no reliable predictive and prognostic markers based on morphology and immunohistochemistry. Comprehensive epigenetic and genetic characterization of non-spinal paragangliomas revealed a diversity of driver alterations affecting multiple genes and pathways and resulted in the establishment of molecularly defined subtypes correlating with clinical out- come. Moreover, at least one-third of non-spinal paragangliomas are associated with inherited cancer susceptibility syndromes, which is the highest rate among all tumor types. Paragangliomas of the central nervous system instead occur almost exclusively in the cauda equina and are considered non-familial. However, genetic and epigenetic alterations in spinal paragangliomas have not been investigated so far. In order to gain further insights into the molecular background of cauda equina paragangliomas and their ontogenetic relationship to non-spinal paragangliomas and other neuroendocrine tumors, we investigate a comprehensive series of cauda equina paragangliomas using a combination of whole exome sequencing and genome-wide DNA methylation profiles. We further aim to identify molecular risk factors for better predicting clinical outcomes and druggable targets for future personalized therapy strategies in patients with malignant tumors.
Dr. med. Vera Seidel
Charité – Universitätsmedizin Berlin, Department of Obstetrics
Email: vera.seidel@charite.de
Fields of Research
- Infectious Diseases in Pregnancy
- Migrant Health in the Context of Obstetrics and Gynecology
Project Title
Maternity Care for Migrant Women in Berlin – Perceptions of Healthcare Professionals and Patients
Project Description
Berlin is a multicultural city and recently migration numbers are further increasing. Studies in Berlin have shown that communication problems are the principal source of doctor’s dissatisfaction in doctor-patient encounters in emergency departments (Babitsch et al. 2008). Low Ger- man-proficiency correlates with less frequent use of antenatal care (Brenne et al. 2015) and dissatisfaction with inpatient hospital care on the side of migrant women (Borde et al. 2002). Migrant women have higher rates of overweight (Reiss et al. 2015) and anemia, less frequently receive peridural anesthesia during birth (David et al. 2006) and their crash cesarean section rates are higher (David et al. 2015). Migrant women in Australia have a less satisfying birth experience (Small et al. 2002). Migrant women from third world countries in Sweden have higher levels of stress in the first year after birth (Fabian et al. 2008). Causative factors for these disparities need to be identified in order to design targeted interventions. This study aims at exploring the perceptions and experiences of medical personnel and migrant women especially in the context of limited German-proficiency during labor to inform policy and clinical practice. A quantitative survey and a qualitative design using grounded theory methodology are currently in progress. In a second step, an intervention study is planned to improve the obstetric care for migrant women with the targeted use of modern communication technology.
Dr. med. Yuliya Sharkovska
Charité – Universitätsmedizin Berlin, Department of Neonatology
Email: yuliya.sharkovska@charite.de
Fields of Research
- Cortical Development
- Hyperoxia‐Induced Immature Brain Injury
- Premature Birth and Cognitive Impairment
Project Title
The Effects of Neonatal Hyperoxia on Cortical Development in Immature Brains and Genesis of Psychiatric Disorders
Project Description
Very preterm birth has been associated with an increased risk to develop cognitive and social-emotional disorders. Premature infants are often exposed to supraphysiologic concentrations of oxygen. While arterial oxygen tension in utero is maintained at low levels between 24 and 28 mm Hg, premature birth into room air causes a several-fold increase in arterial oxygen tension in preterm infants to 65 mmHg and higher, even without supplemental oxygen. The exposure to this hyperoxic ex utero environment may affect the immature brain during neuronal differentiation and maturation processes. In humans, the period of fastest brain growth is observed during the last 3 months of a full-term pregnancy. In newborn mice and rats, in contrast, this brain growth spurt occurs be- tween postnatal days 2 and 10. Therefore, rodents have been used as an experimental model to investigate the mechanisms of vulnerability in the developing brain. We are applying an established neonatal hyperoxia model in newborn VGAT–Venus transgenic and in WT mice providing 48 h exposure to fourfold increased oxygen concentration (80% O2) from P5 to P7, followed by recovery in room air until young adult ages. With the current project, we aim to analyze the consequences of neonatal hyperoxia on following aspects of neonatal brain development in immature animal model:1) the neurobiological mechanisms through which hyperoxia affect cortical neurogenesis and may lead to the development of cognitive disorders in preterm children, 2) the neuroprotective effects of erythropoietin on hyperoxia-induced brain injury, with the aim of improving neurobehavioral and cognitive outcomes after preterm birth.
PD Dr. med. Michael Sigal
Charité – Universitätsmedizin Berlin, Medical Department, Division of Hepatology and Gastroenterology
Email: michael.sigal@charite.de
Fields of Research
- Gastrointestinal Stem Cells
- Helicobacter Pylori
- Gastrointestinal Microbiota
Project Title
Mechanisms of Gastric Stem Cell Control Upon Infection and Carcinogenesis
Project Description
The gastric epithelium is characterized by rapid self-renewal. Long-lived Lgr5-expressing stem cells that are localized in the base of the stomach antral glands constantly regenerate the epithelium. Lineage tracing experiments have shown that stomach glands are regenerated by Lgr5+ stem cells for a year or more, demonstrating the longevity of these cells (Barker et al., 2010). In addition to their physiological relevance, these long- lived cells also appear to be critical in the process of carcinogenesis (Barker et al., 2009). Accordingly, Lgr5+ cells have been reported to expand and show increased evidence of DNA damage in patients with gastric cancer (Uehara et al., 2013). Chronic infection with the gastric pathogen H. pylori is the major known risk factor for the development of gastric cancer (Blaser et al., 1995; Par- sonnet et al., 1997). Hypothesizing that H. pylori affects gastric stem cells, we have previously used mice that express GFP under the Lgr5 promoter to show that al- though they are located at the very base of the gland, H. pylori is able to directly colonize and grow on the inter- cellular junctions of stem cells (Sigal et al., 2015). Infection induces a two-fold increase in the number of stem cells per gland unit and a significantly higher proliferative activity. Lineage tracing experiments revealed that infection induced a significant increase of the turnover kinetics of stem cells, resulting in the repopulation of entire glands within five instead of ten to 14 days, finally resulting in severe glandular hyperplasia (Sigal et al., 2015). An unresolved question is how stem cell number, their division rate, and fate determination are con- trolled under physiological conditions as well as upon infection. I plan to characterize the gastric stem cell microenvironment, the so-called stem cell niche, under physiological conditions as well as upon infection to understand how stem cell number, proliferative activity, and fate determination are controlled. I will focus on Wnt signaling, study its cellular organization and unravel how alterations of Wnt signaling affect stem cell and tis- sue homeostasis. Further, using an unbiased approach I will investigate how the myofibroblasts that surround the stem cells affect stem cell behavior.
PD Dr. med. Bruno Valentin Sinn
Charité – Universitätsmedizin Berlin, Institute of Pathology
Email: bruno.sinn@charite.de
Fields of Research
- Response Prediction in Breast Cancer
- TH4‐Response
Project Title
Evaluation and Integration of Molecular Assays to Address Clinical Problems in Breast Cancer
Project Description
Greater availability of personalized treatment strategies for breast cancer requires a better prediction of therapy response to select treatment for individual patients. A large number of patients does not respond well to chemotherapy, especially those with hormone receptor- and HER2-negative disease. Many biological determinants of response remain unknown and there are no reliable markers to predict the outcome. In addition to chemotherapy, immunotherapies yield promise in the treatment of breast cancer and reliable measures of tumor-immunological activity are required to select patients. Tissue in pathology is fixed in formalin and em- bedded in paraffin and numerous annotated clinical trial cohorts are available. The use of high-dimensional techniques like next-generation sequencing can be challenging due to formalin-induced alterations. At the same time, the accessibility of this tissue by modern techniques is crucial for translational research and for the successful translation of gene assays into clinical practice. In this project, we aim to study the mechanisms of sensitivity and resistance to neoadjuvant chemotherapy with or without immune checkpoint inhibition. We will develop robust assays for formalin-fixed paraffin tissue to facilitate the translation into clinical practice. First, we will evaluate the use of RNA sequencing on formalin-fixed paraffin samples. Using paired pre-therapeutic and intermediate biopsies obtained during neoadjuvant therapy, we will then characterize molecular changes that occur under chemotherapy with or without immune checkpoint inhibition. This will allow us to define therapy-induced alterations associated with therapy response. In addition, we will test pre-defined gene signatures of immunological activity as markers for response to immune checkpoint inhibition. We will include the newly discovered markers into customized targeted assays to extend the analysis to a larger number of samples and future clinical trials.
Dr. med. Cornelia Skowronek
Charité - Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology
Email: cornelia.skowronek@charite.de
Fields of Research
- Parkinson Syndromes
- Immunoneuropathology
- Autonomic Nervous System
Project Description
Synucleinopathies are neurodegenerative diseases as Parkinson Syndromes (e.g. Parkinson’s Disease (PD) and Multiple System Atrophy (MSA)). Pathological α-Synuclein (SNCA) phosphorylation induce misfolding and deposition of insoluble intracellular pSNCA aggregates. Differential diagnosis of Parkinson Syndromes is based on clinical criteria. However, a definite discrimination can only be assessed post-mortem by means of different cerebral pSNCA aggregate localization (neurons vs. glial cells). In contrast to MSA, PD includes affection of peripheral nervous system. For the first time, our group could discriminate PD and MSA by detection of pSNCA in dermal sympathetic nerve fibers in vivo. All PD patients revealed a positive pSNCA immunoreactivity and all MSA patients were pSNCA negative. However, other groups report on different methods with significantly variable sensitivity and/or specificity that prevent a successful use in a clinical routine so far. Putative reasons are different biopsy locations, diverse staining protocols, pSNCA antibodies and nerve fiber type. In this project, we will implement dermal Serine 129 pSNCA in sympathetic nerve fibers as a new biomarker for early and definite differential diagnosis of PD in clinical routine. We will state a definite, highly sensitive and specific proto- col for patients suffering from Parkinson Syndromes, including standardized skin punch biopsy location, the most sensitive pSNCA antibody, and the right target fiber type. Moreover, we will improve the understanding of pSNCA dependent neurodegeneration in the peripheral nervous system (PNS), by correlating functional features of affected nerve fibers types (autonomic vs. somatosensory) with their histopathological pattern to assess differences in morphology, distribution, and quantification of pSNCA in PNS vs. CNS. This project will provide a new in vivo diagnostic tool for PD and will con- tribute to adjusting the guidelines and diagnostic consensus criteria.
PD Dr. med. Malte Spielmann
Prof. Dr. med. Mirjam Stahl
Charité – Universitätsmedizin Berlin, Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine
Email: mirjam.stahl@charite.de
Fields of Research
- Chronic lung disease
- Diagnostics in Cystic Fibrosis and Innovative Therapies
Project Title
Characterization of Early Cystic Fibrosis Lung Disease and Innovative IITs
Project Description
Cystic fibrosis (CF) lung disease starts early in the first months of life with structural changes, lung function impairment and neutrophilic inflammation. We established TRACK-CF as a longitudinal cohort (clinicaltrials. gov NCT02270476) to investigate the onset and progression of CF lung disease in infants and children with CF. Clinical data of the deeply phenotyped TRACK-CF cohortwill be used in conjunction with blood and throat swab samples of study participants to identify influencing factors (risk or protective ones) of early CF lung disease. To achieve this goal, several approaches are planned: (i) Investigation of the longitudinal relationship between the multiple-breath washout (MBW)-derived lung clearance index (LCI) and findings in magnetic resonance imaging (MRI), graded by a scoring system, to better understand the relationship between functional and structural pathologies in the established TRACK-CF cohort; (ii) relate findings in the course of LCI and MRI scores with microbiological results and clinical findings in the deeply phenotyped TRACK-CF participants; and (iii) investigation of proteomic and metabolomic signatures in blood samples of distinct patient groups with CF: a) Based on previous results, we will compare frequent
exacerbators vs. stable patients, b) patients with extreme phenotypes, and c) children diagnosed following newborn screening (NBS) vs. children diagnosed due to clinical signs of CF. Characterization of potentially avoidable or influencable risk factors for disease progression can help to further reduce disease progression and improve long-term outcomes of patients with CF.
Identification of non-invasive biomarkers that have the potential to indicate e.g. a deterioration early will be useful for clinical management. In addition, such biomarkers could be used as endpoints in future studies on preventive therapies. Based on results from a preclinical study in a mouse model with CF-like lung disease, we have already developed an innovative IIT on efficacy and safety of anakinra in people with CF, which we are currently conducting within the German Center for Lung Research, using MBW and MRI as endpoints.MD/PhD Leon Amadeus Steiner
Charité – Universitätsmedizin Berlin, Department of Neurology and Experimental Neurology
Email: leon-amadeus.steiner@charite.de
Fields of Research
- Deep Brain Stimulation
- Synaptic Mechanisms
- Human Single Cell Research
Project Title
Synaptic Mechanisms to Retune Inhibitory Control of the Subthalamic Nucleus in Patients with Parkinson’s Disease
Project Description
Deep brain stimulation (DBS) of the Subthalamic Nucleus (STN) is an effective treatment for Parkinson’s Disease symptoms. However, DBS only provides transient relief of symptoms, which rapidly return when stimulation is discontinued. To advance DBS therapy, a more thorough understanding of fundamental mechanisms is needed. Evidence from rodent studies has shown the potential of microcircuit interventions to induce long-lasting recovery of movement. Specifically, selective stimulation of inhibitory projections to the STN have been implicated in these effects. In humans, there is exciting new evidence that deep brain stimulation may serve to retune inhibitory synaptic control of basal ganglia structures. At present, however, inhibitory synaptic plasticity in basal ganglia structures has exclusively been studied in STN output structures in humans. In the rat, we have previously shown that the input of inhibitory projections is sustained at high stimulation frequencies in contrast to rapidly depressed excitatory input. Capitalizing on the unique opportunities of intraoperative microelectrode and human single-neuron recordings, this study aims to elucidate effects of the activation of inhibitory projections to STN by DBS in humans. Understanding the underlying physiological mechanisms of this aspect of DBS may be critical in optimizing DBS stimulation paradigms.
Dr. med. Helena Stengl
Dr. med. Kim N. Stolte
Charité – Universitätsmedizin Berlin, Institute for Dental, Oral and Maxilary Medicine
Email: kim-natalie.stolte@charite.de
Fields of Research
- Oral barrier
- Inflammatory diseases of the oral cavity
- Anti-inflammatory therapy
Project Title
Expression and Regulation of S100A7/Psoriasin in Oral Lichen Planus
Project Description
Lichen planus is a chronic inflammatory autoimmune disease. Signs of oral lichen planus (OLP) range from mild inflammation to destruction of the epithelial surface with painful sores and may result in the development of squamous cell carcinoma. Despite the well-characterised clinical manifestations of LP, the pathogenesis is still largely unknown and there is no curative treatment for
OLP. This project aims to help elucidate the aetiopathogenesis of OLP by investigating the regulation of mediators of barrier function in order to develop new therapeutic approaches. In this context, the project aims to characterise the expression and regulation of S100A7/ psoriasin in human oral epithelium of healthy donors and patients with oral lichen planus. The functional analyses
of the tissue samples will include analysis of mRNA expression by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and protein expression by immunohistochemistry (IHC). The data will be validated by in vitro experiments (RT-qPCR, IHC, ELISA). Furthermore, these expected results will be useful to refine three-dimensional inflammatory models of the oral mucosa to provide an ethically acceptable alternative to human biopsies and animal experiments.Dr. med. Kaspar Josche Streitberger
Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology
Email: kaspar‐josche.streitberger@charite.de
Fields of Research
- Neuroprotection
- Prognostication After Cardiac Arrest
- Cold Shock Protein
Project Title
Hypothermia and Neuroprotection: A Role for Cold-Shock-Proteins?
Project Description
The aim of this research study is the investigation of cold-shock protein RNA-binding-motif-protein 3 (RBM3) and its neuroprotective role. The expression of RBM3 is -unlike most other proteins- induced by hypothermia. RBM3 is discussed to be a promotor of global protein synthesis as well as specific proteins with neuroprotective effects of which only a few are known. First described by Derry et al. in 1995 it is expressed ubiquitously in human cells and its pathophysiological function is so far only partially understood. Our goal is to investigate the role of RBM3 and its neuroprotective function during hypothermia using a multimodal approach in cooperation with the research group »Hypothermia and Neuroprotection« at the DHZB, the Department of Neuropathology and the Department of Nephrology and Intensive Care Medicine. Our core projects include the characterization of RBM3 serum concentration in patients treated with mild therapeutic hypothermia after cardiac arrest and resuscitation. Changes in the course of hypothermia could function as a possible marker for neuronal cell damage and/or for the monitoring of hypothermia treatment. Within our study, we also focus on the investigation of RBM3 expression in human brain tissue. Our goal is to quantify and localize RBM3 within the human brain in correlation with pathological quantification/markers of neuronal cell damage giving us insights into possible neuroprotective effects of RBM3 in the adult human brain. In cooperation with the research group »Clinical and experimental Epileptology« we aim to establish human brain slice cultures to analyze RBM3 regulation under hypothermia and hypoxia. The characterization of the RNA expression and RBM3 protein synthesis could provide the groundwork for subsequent studies investigating the optimum neuroprotection through hypothermia.
Dr. med. Rahel Maria Strobel
Charité – Universitätsmedizin Berlin, Department of General, Visceral and Vascular Surgery
Email: rahel.strobel@charite.de
Fields of Research
- Visceral surgery
- Oncology
- Patient-reported quality of life
Project Title
NOTE – Necessity of Protective Ileostomy in Rectal Resection?
Project Description
Low anterior rectal resection for rectal cancer goes along with the creation of a protective ileostomy in most of the cases. A protective ileostomy can cause an immense deterioration of the patients‘ quality of life. Furthermore, postoperative complications such as excoration of the peristomal skin, peristomal abscesses, prolapse of the ileostomy or renal failure because of high fl uid losses occur in nearly 15%. Ileostomy reversal requires surgery once again with inherent hospital stay, healthcare costs and possible complications. But the patient’s safety in rectal resection must be mentioned as well. There are data that a protective ileostomy can lower septic complications caused by insufficiency of the rectal anastomosis. To further evaluate the necessity of protective ileostomy in low anterior rectal resection we conduct the NOTE trial which is a multicentric, prospective, randomised-controlled trial comparing patients with and without protective ileostomy undergoing rectal resection because of rectal cancer. Primary hypothesis says that patients without protective ileostomy have a better quality of life one year after rectal resection than patients with protective ileostomy measured by the mean score of the category »physical function« of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). There will be 224 patients overall, 112 each group, when a dropout rate of 10% is assumed. After randomisation of 25 patients in each group a safety analysis regarding operative revision because of insufficiency of rectal anastomosis will be conducted. All, inclusion criteria, surgical technique and perioperative management will be standardized. Three year follow-up of the patients includes both clinical examination and questionnaires as well as oncological outcome.
PD Dr. med. Benjamin Strücker, FEBS
Dr. med. Heiner Stuke
Charité – Universitätsmedizin Berlin, Department of Psychiatry and Neurosciences
Email: heiner.stuke@charite.de
Fields of Research
- Schizophrenia
- Dopamine
- Functional MRI
Project Title
The Role of Dopamine in Psychosis-Related Perceptual Aberrations
Project Description
Paranoid schizophrenia is a serious mental illness with poorly understood etiology. Although acoustic hallucinations are the classic leading symptom of schizophrenia, changes in visual perception are also typically found, the potential of which as a diagnostic marker could be underestimated. It is believed that these symptoms are associated (among other things) with excessive dopaminergic neurotransmission. A cognitive mechanism that has been related to the development of hallucinations is an increased willingness to perceive significant structures in noisy sensory signals. The background to this consideration is the knowledge of perception research that the subjectively experienced clear perception is the result of a calculation process that uses probabilities, context information and signals from other sensory modalities in order to generate reliable statements about the environment from an extremely noisy sensory signal. A constant challenge in this calculation process is the distinction between really significant signals and pure
sensory noise. Hence, a reduced ability to differentiate between signal and noise and an increased tendency to interpret noise as a meaningful signal can result in a tendency to hallucinations. A number of empirical studies confirm, especially in the domain of acoustic perception, an increased perception of signal in noise in people with psychosis, psychosis proneness or isolated hallucinosis. The neurophysiological aberrations leading to such an increased perception of meaning in noise are largely unexplained. This concerns both the aspect of the involved neurotransmitter systems as well as the functionally affected brain areas. The present study aims to contribute to closing this gap by firstly examining the specific effect of a dopamine-enhancing drug modulation compared with placebo in healthy volunteers and secondly the involvement of specific brain areas through
functional MRI during an face detection task.PD Dr. med. Thi Minh Tam Ta
Charité – Universitätsmedizin Berlin, Department of Psychiatry
Email: thi‐minh‐tam.ta@charite.de
Fields of Research
- Neurobiology of Depression
- Peripheral Cytochrome P 450 Activity
- Depression Pathogenesis
Project Title
Influence of Peripheral Cytochrome P-450 2C19 Activity on Depression: A Functional Study in two Distinct Ethnic Groups
Project Description
Various independent findings indicate a direct role of altered Cytochrome P450 activity, especially CYP 2C19 in depression pathogenesis which is independent of pharmacokinetic effects. This involvement is apparently mediated by an impact on the metabolism of endogenous substrates. Translational approaches and initial clinical findings on CYP2C19 showed the presence of a »fast« metabolism (UM) in humans are associated with depressive behavior and reduced hippocampal volumes. Besides drugs lifestyle factors such as smoking, nurture and medicinal herbs can also influence the CYP 2C19 enzyme activity. Interestingly various traditional plant based drugs, which are widespread in Asia have a strong inhibition effect on CYP2C19 enzyme activity. Such influence factors are entirely neglected by genotyping. In addition to variables such as sex, age, substance consumption and eating habits, there is a high degree of ethnic variability, particularly in the activity of CYP2C19 isozymes. To evaluate the recent findings, the proposed study of an additional Southeast Asian population (Vietnamese) is ideal. Until now, a link between CYP450 2C19 genotype and depressive symptoms, independent of the influence of lifestyle and ethnicity has been studied primarily by genotyping. The methodological restriction would be that the genetic analysis only allows an indirect conclusion of the activity of the CYP450 2C19 enzyme. Therefore, our project investigates for the first time the functional link between the CYP 2C19 enzyme activity and depressive symptoms by the measurement the functional enzyme activity in the peripheral blood in Vietnamese and German patients with depression. The activity measurements on patient-specific cells, in contrast to the exclusive genotyping, is also influenced by epigenetic regulation, induction or inhibition. This functional approach can also provide valuable evidence of potentially usable »druggable targets« which leads to the development of personalized treatment for the patients suffering from depression.
Dr. med. Christoph Tabeling
Charité – Universitätsmedizin Berlin, Department of Infectious Diseases and Respiratory Medicine
Email: christoph.tabeling@charite.de
Fields of Research
- Pulmonary hypertension
- Pulmonary circulation
- Asthma
Project Title
Role of Spleen Tyrosine Kinase (Syk) in Pulmonary Arterial Hypertension (PAH)
Project Description
Pulmonary arterial hypertension (PAH) is a fatal condition characterized by pulmonary vasoconstriction and pulmonary arterial remodeling leading to increased pulmonary vascular resistance and ultimately right heart failure. Intense research within the past three decades led to successful translation of pharmacological compounds, which are able to improve both quality of life and survival of PAH patients. However, despite modern PAH-specific therapy, PAH remains to be a lethal disease and further research is required. From previous studies we learned that in the airways the non-receptor tyrosine kinase spleen tyrosine kinase (Syk) promotes inflammation, smooth muscle cell proliferation and contraction (Tabeling, C. et al. Allergy 2017 Jul;72(7):1061-1072). However, little is known about the expression and role of Syk in the vascular compartment of the lung. Therefore, in this ongoing project, we analyze Syk expression and function in the pulmonary vasculature and its possible involvement in the pathogenesis of PAH. To date, Syk expression was assessed in human (PAH vs. donor) and murine lungs by immunofluorescence and spectral confocal microscopy. Syk function was analyzed in human precision-cut lung slices (PCLS) and in isolated perfused lungs of wildtype mice or mice deficient in eNOS, PKCα or mast cells
with or without inhibition of Syk, protein kinase C (PKC), rho kinase and/or nitric oxide (NO) synthase. Pulmonary vascular hyperresponsiveness was investigated following induction of pulmonary Th2 inflammation. Our data identify Syk as a central regulator of pulmonary vasoconstriction. Syk was expressed in pulmonary arterial smooth muscle cells of both control and PAH lungs. Syk inhibition diminished pulmonary vasoconstriction in human PCLS and in isolated mouse lungs independent of eNOS, PKCα or mast cells. In preconstricted lung vasculature, Syk inhibition rapidly reversed vasoconstriction in a NO-independent manner. Pulmonary vascular hyperresponsiveness was markedly reduced following Syk inhibition. Thus, Syk may be a promising target in PAH therapy and the effects of Syk inhibition on pulmonary arterial remodeling and pulmonary hypertension will be further analyzed in this project. Moreover, we attempt to further characterize the intracellular Syk-mediated signaling cascade leading to pulmonary arterial smooth muscle cell contraction.PD Dr. med. Dorothea Terhorst-Molawi
Charité – Universitätsmedizin Berlin, Department of Dermatology, Venerology and Allergology
Email: dorothea.terhorst@charite.de
Fields of Research
- Drug Delivery
- Dendritic Cells, Macrophages and MasT‐cells
- Skin Immunology
Project Title
Laser-Assisted Dermal Drug Delivery
Project Description
Intradermal drug-delivery represents an attractive mode of application because of the skin’s easy accessibility and its high and dense network of immune cells. By using a fractionated ER:YAG laser, we can generate micropores of different depth in the skin, which allows the deposition of molecules with high precision. Dermal dendritic cells (DCs) expressing the XCR1 chemokine receptor, also known as CD103+ or CD8α+ DCs, excel in the presentation of extracellular antigens to CD8+ T-cells. By creating laser-generated micropores through the epidermis, we targeted a model protein antigen fused to XCL1, the ligand of XCR1, to dermal XCR1+ DCs and induced antigen-specific CD8+ and CD4+ T-cell responses. In a murine tumor model, we have shown that laser-assisted drug delivery induces a strong local as well as a systemic anti-tumor response, which seems to be superior to classical needle-based drug delivery. We are now aiming to better understand the molecular mechanisms of this enhanced effect of laser-assisted dermal drug delivery. Furthermore, we are planning to apply this method in patients with different skin diseases. The use of this new laser technology, therefore, represents a scientific approach to tackle the clinical challenge of finding the best route of application and optimizing the therapeutic effect.
Dr. med. Dorothea Theilig
Charité – Universitätsmedizin Berlin, Department of Radiology (including Pediatric Radiology)
Email: dorothea.theilig@charite.de
Fields of Research
- Endoscopic Lung Volume Reduction
- Quantitative CT Scan Analysis
- Chronic Obstructive Pulmonary Disease
Project Title
Evaluation and Optimisation of Endoscopic Lung Volume Reduction Therapy in Patients With Pulmonary Emphysema by Means of Quantitative Lung Parenchyma Analysis
Project Description
Chronic obstructive pulmonary disease (COPD), which is often accompanied by emphysema in its final stages, is one of the leading causes of death worldwide. Air trapping in the alveoli causes permanent enlargement of the airspaces distal to the terminal bronchioles thereby decreasing the surface area for gas exchange. Overall increased lung volume, in turn, leads to impaired breath- ing mechanics furthering the problem. A more recent therapeutic approach to severe COPD with emphysema is endoscopic lung volume reduction (ELVR) therapy. ELVR works by inducing atelectasis in one lobe thereby allowing the rest of the lung to expand and breathing mechanics to be somewhat restored. The aim of this project is to im- prove the understanding of pulmonary emphysema and to evaluate and optimize ELVR therapy. To this end, we will make use of the software MeVisPULMO 3D (Fraunhofer MEVIS, Bremen, Germany), which allows quantification of emphysematous lung parenchyma and semi-automatic lung lobe segmentation of CT scans of the lung. Factors that influence the outcome of ELVR are sought after as well as selection criteria for the targeted lobe. Already established factors that have an impact on the outcome of ELVR are emphysema heterogeneity and collateral ventilation of the targeted lobe. How to determine these factors in the best possible way in clinical routine will also be part of this research project.
Dr. med. Alexander Thieme, M.Sc.
Charité – Universitätsmedizin Berlin, Department of Radiation Oncology and Radiotherapy
Email: alexander-henry.thieme@charite.de
Fields of Research
- Digital Health
- App Development
Project Title
Electronic Patient-Reported Outcomes for Relapse Detection in Cancer Patients and Mitigation of the Novel Coronavirus Pandemic
Project Description
Electronic Patient-Reported Outcomes (ePROs) promote patient-centered care by collecting and incorporating patient-reported information into clinical settings. At the heart of this digital health project, an open-source ePRO application (app) was developed with the flexibility to be adapted to various clinical situations and a focus on ease-of-use for the patient. Two different use cases are evaluated for this app: 1.) relapse detection for cancer patients, 2.) risk evaluation of users potentially infected with the novel coronavirus (SARS-CoV-2). Regarding use case 1, standard of care for relapse detection in cancer patients usually involves follow-up visits in fixed intervals.
This leads to unnecessary prolongation of relapse detection which can have a deleterious effect on the oncological outcome. ePROs facilitate that patients enter symptoms directly into a database that can be evaluated in real-time. Especially, patients with locally advanced head and neck squamous cell carcinoma (HNSCC) may profit from earlier relapse detection which is seen in 15-50% of the cases. HNSCCs are known to proliferate rapidly and deferred treatment can result in stage progression. Recurrent stage is known to be the most important parameter regarding overall survival. A model is built based on ePROs to detect patterns with the goal of earlier relapse detection with a lower recurrent stage. Machine learning methods are used for model creation in collaboration with Stanford University. For use case 2, the app has been published under the name CovApp and could demonstrate the ability of fast deployment during the onset of the novel coronavirus pandemic and scalability to a larger number of users. CovApp provided individualized recommendations based on ePROs regarding laboratory testing, probability of severe covid-19, and guidance for several million users in Germany and internationally. At the hospital, increased efficiency could be achieved by reducing the time necessary for anamnesis by providing the function to scan ePROs directly from the patient’s smartphone via QR code. Hereby, it contributed to identify and interrupt infection chains, optimize health care resources and provide crucial information to the general population, especially to high-risk patients. Further development aims to evaluate the project's big data for local outbreak detection and case number prediction.Isabelle Träger
Charité - Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Hämatologie, Onkologie und Tumorimmunologie
Email: isabelle.traeger@charite.de
Fields of Research
- Translational hematology and oncology
- B-cell lymphoma
- Genetic screening
Project Title
Identification of rational SUMO pathway targeted combination therapies for aggressive B cell lymphoma
Project Description
SUMOylation is a post-translational protein modification that controls the localization, stability and activity of target proteins. SUMOylation has emerged as a crucial mechanism for regulation of cell cycle progression, maintenance of genome integrity, control of gene expression and for immune responses to various biological stresses. The conjugation of SUMO (SUMO1, SUMO2 or SUMO3) to cellular proteins proceeds by a multi-step enzymatic cascade involving a dimeric E1 SUMOactivating enzyme (SAE1/UBA2), a single E2 SUMO-conjugating enzyme (UBC9) and a limited set of SUMO-E3 ligases. SUMOylation is activated in response to stress.
Even more than their healthy counterparts, cancer cells are subject to various environmental impacts like replicative stress, hypoxia and specifically the antitumor immune response of the host immune system. Dysregulation of oncogenes such as MYC, which is highly expressed in B cell lymphoma, provokes activation of the SUMO pathway and shifts the SUMO equilibrium to a hyperSUMOylation state. Thus, inhibition of SUMOylation impairs MYC-dependent tumorigenesis. Therefore, it seems reasonable that SUMOylation inhibition has a therapeutic benefit.
TAK-981 (Subasumstat) is a first-in-class SUMOylation inhibitor currently being tested in clinical trials in patients with refractory non-Hodgkin’s lymphoma and solid tumors.
Considering the average number of 70 genetic alterations and many other transcriptional and epigenetic dysregulated genes in diffuse large B-cell lymphoma (DLBCL), it can be assumed that there is a genetic and non-genetic background for sensitivity or resistance of cells to the drug TAK- 981.
Therefore, my project focuses on the investigation of TAK-981 resistance in DLBCL cell lines using genome-wide CRISPR/Cas9 screens to identify resistance-mediating genetic networks. Ultimately, I aim to develop combination therapies that effectively cross resistance barriers in DLBCL and thus
lead to new treatment options for DLBCL patients.Dr. med. Eva Tranter
Charité – Universitätsmedizin Berlin, Department of Hematology, Oncology and Cancer Immunology
Email: eva.tranter@charite.de
Fields of Research
- B cell receptor sequencing
- B cell reconstitution
- Bone Marrow Niche
Project Title
Characterization of the Human Bone Marrow Niche and Immune Reconstitution after Allogeneic Stem Cell Transplantation
Project Description
Despite the rapid advances in cancer therapies, allogeneic hematopoietic stem cell transplantation (alloHSCT) still remains an integral part of curative therapeutic strategies in the field of hematology. During alloHSCT the recipient is conditioned with high-intensity chemotherapy and/or irradiation in order to deplete residual tumor cells and to facilitate the rooting of donor’s hematopoietic stem cells within the recipient’s bone marrow niche. Recent studies were able to show that the interplay between non-hematopoietic bone marrow and hematopoietic cells is essential for an efficient immune reconstitution after transplantation. Several factors such as the occurrence of bone marrow graft-versus-host disease as well as irradiation have been identified to hamper the process of immune and B cell reconstitution due to niche damage, resulting in a higher risk for infections and thereby increased morbidity and mortality after alloHSCT. We are underway to conduct a full characterization of the human bone marrow niche before, during and after alloHSCT via immunofluorescence confocal microscopy as well as single-cell analyses. Our goal is to decipher the therapy-induced alterations and reconstitution of the bone marrow niche with focus on the interaction of immune and stroma cells. We will further implement flow cytometry analyses of B cell subpopulations in peripheral blood and B cell receptor sequencing at various time points before and after alloHSCT, in order to evaluate the B cell regeneration and BCR repertoire after transplantation. Pairing these findings with information on clinical features, we hope to shed some light on the pathomechanisms of bone marrow niche damage and hampered B cell reconstitution and to develop individual strategies for improving humoral immunity after allogeneic HSCT.
Dr. med. Christoph Treese
Charité – Universitätsmedizin Berlin, Division of Gastroenterology, Infectiology and Rheumatology
Email: christoph.treese@charite.de
Fields of Research
- Gastrointestinal Oncology
- Metastasis
- Therapy Prediction
Project Title
Development of Prognostic and Predictive Biomarkers for Gastric Cancer
Project Description
Despite radical tumor resection with extended lymphadenectomy, approximately 40% of patients with gastric cancer develop a disease relapse after initial curative treatment. Where in early tumor stage patients are treated only by surgery, patients with locally advanced stages get an escalated therapy with chemotherapy and surgery. This additional treatment leads to the survival benefit of 10% for these patients. In a retrospective analysis, we could show in 76 patients with gastric cancer that 12,8% of the patients had a complete response to the preoperative treatment and 89% of them were alive after 5 years. In contrast to these patients, 11.5% had a disease progression under this treatment and a decreased survival of only a few months. To improve the survival of patients with gastric cancer we need on the one hand prognostic biomarkers to identify high-risk tumors in early tumor stages for escalating the therapy. On the other hand, we need also predictive biomarkers to identify therapy responders and non-responders for treating patients only with effective chemotherapy. In this project, we analyze the role of the prognostic oncogene MACC1 (metastasis-associated in colon cancer-1) for gastric cancer. On the basis of MACC1 as a model biomarker we are developing an experimental platform to analysis biomarkers on the level cell lines in vitro and in an orthotopic cell line derived xenograft models (CLDX) in vivo. Furthermore, we are creating patient-derived xenografts (PDX) and collecting tumor samples from a large gastric cancer population. In a second step, we would like to identify new prognostic markers by performing next-generation sequencing in a large gastric cancer cohort. On the base of the experimental platform describe above we would like to prove the quality of these biomarkers. The development of predictive biomarkers is performed in collaboration with the Max Plank Institute for molecular genetic (AG Prof M. Schweiger). In this project, we are collecting biopsies of patients with gastric cancer before and after the first cycle of chemotherapy. By analyzing the samples with RNA-Seq and correlating the reaction profiles with the histopathologic remission after three cycles of therapy, we hope to find specific reaction pro- files to predict the response to chemotherapy.
Dr. med. Sevtap Tugce Ulas
Charité – Universitätsmedizin Berlin, Department of Radiology (including Pediatric Radiology)
Email: sevtap-tugce.ulas@charite.de
Fields of Research
- Arthritis Imaging
- Dynamic Computed Tomography
- Radiomics
Project Title
Evaluation of wrist patho-biomechanics in inflammatory joint diseases with 3D radiomics using 4D-CT as reference standard
Project Description
The ever-advancing technical development in the field of computed tomography (CT) is constantly opening up new possibilities for generating additional information. The most modern CT detectors enable the acquisition of images under motion. This allows excellent assessment of both static and dynamic phenomena of three-dimensional objects within a complex anatomy. The carpus is of particular interest for four-dimensional CT (4D-CT or CT cinematography) because certain motion patterns cannot be accurately visualized with conventional cinematographic techniques. Damage to the carpal ligaments has been described for a number of diseases, including inflammatory joint diseases. This structural damage can lead to permanent loss of function and secondary osteoarthritis, which can perpetuate symptoms despite sufficient anti-inflammatory therapy. For this reason, 4D-CT has been developed for the assessment of dynamic, biomechanically relevant stages of carpal ligament lesions and evaluated to the point that it can be used as a noninvasive alternative in this research project. Furthermore, radiomics is of increasing importance in modern medicine, providing imaging-derived biomarkers by extraction of quantitative features beyond human recognition. Segmentation processes can then be used to generate multidimensional features indicating destruction of the microscopic architecture. In this way, radiomics can contribute to a better understanding of remodeling processes and differentiate ruptures and biomechanical instabilities using 4D-CT as standard of reference. This research aims to further understand the patho-biomechanics of the wrist in patients with inflammatory joint disease using radiomics analysis and to compare these findings with healthy controls.
Dr. med. Christoph van Riesen
Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology
Email: christoph.van‐riesen@charite.de
Fields of Research
- Movement Disorders
- Parkinson ́s Disease
- Basal Ganglia
Project Title
Thalamic Deep Brain Stimulation as a Novel Treatment for Rapid-Onset Dystonia Parkinsonism
Project Description
Rapid-onset dystonia-parkinsonism (RDP) is a rare neurologic disease for which there is currently no treatment. So far the pathophysiology of the disorder is incompletely understood and has not been explored in detail. Only recently it has been discovered that RDP is caused by an autosomal-dominant mutation in the alpha-3 subunit of a sodium-potassium ATPase pump. First studies on the ouabain-mouse model of RDP suggest that the symptoms are mediated by a particular disease mechanism that involves the combined dysfunction of the cortico-basal ganglia loop and the cerebellum. Derived from publications by others and us on related movement disorders such as Parkinson ́s disease and dystonia, it can be speculated that pathological neuronal network activity may be of primary importance for the understanding of RDP. Deep brain stimulation (DBS), an innovative neuromodulatory treatment that has been successfully applied to different movement disorders, could be a potential treatment for RDP, although first clinical trials with DBS of the pallidum have not beneficial. The aim of my project is to characterize the pathophysiology of RDP in order to establish DBS as a new treatment of RDP. To reach that goal, I will first record and pharmacologically modulate neuronal network activity from the basal ganglia, the cerebellum, and the thalamus by simultaneous multi-site in-vivo electrophysiology in the ouabain rat model of RDP. Here, the focus will be on local field potentials as well as on single-unit-recordings to better understand how aberrant network activity leads to the debilitating movement disorder. Building on that, I will explore the effect of a tailored DBS treatment of the thalamus on the dysfunctional neuronal network and on the symptomatology in our animal model. By using this approach, I will deepen our understanding of the pathophysiology of RDP and thus help to find the first treatment for RDP.
PD Dr. med. Falk von Dincklage
Charité – Universitätsmedizin Berlin, Department of Anesthesiology and Operative Intensive Care Medicine
Email: falk.von‐dincklage@charite.de
Fields of Research
- Clinical Neurophysiology in Anesthesiology
- Clinical Pain Research
- Medical Information Systems
Project Title
Absence of Clinical Responses to Noxious Stimulation Under General Anesthesia is Not Indicative of an Absence of Nociception
Project Description
In current clinical practice, dosing of analgesics during general anesthesia is performed based on the patient’s responsiveness to noxious stimulation. If a patient moves or exhibits an increase in blood pressure or heart rate in response to a surgical stimulus, the analgesic dose is increased as the clinical responses are considered signs of a neuronal processing of the painful sensory input, which is termed nociception. Accordingly, if a patient shows no clinical responses to noxious stimulation, the analgesic dose is considered sufficient, as the absence of responses is considered indicative of absent nociception. However, we were able to demonstrate in an experimental setting using functional magnetic resonance imaging (fMRI), electroencephalography (EEG) and spinal pain reflexes (NFR) during general anesthesia that nociception persists in the spinal cord and the brain throughout the common clinical doses of anesthetics (von Dincklage et al., Neuroimage 2018). Furthermore, we showed that the assumption that absence of clinical responses is a sure sign of a sufficient analgesic dose is not valid as we demonstrated a persistence of nociception in spinal cord and brain even though the subjects showed no clinical responses to the stimuli (von Dincklage et al., British Journal of Anaesthesia 2018). Also, we showed in a clinical study that higher analgesic doses during general anesthesia seem to be associated with lower rates of chronic pain, which might be explained by a better suppression of pain sensitization processes that might be triggered through intraoperative nociception (von Dincklage et al., European Journal of Pain 2018). Thus, if future studies confirm this connection between persistent nociception during general anesthesia and triggering of chronic pain, the current clinical practice of dosing analgesics according to clinical responsiveness might have to be changed and alternative surrogate measures for nociception during general anesthesia might be required.
PD Dr. med. Maximilian von Laffert
Charité – Universitätsmedizin Berlin, Institute of Pathology
Email: maximilian.von‐laffert@charite.de
Fields of Research
- NSCLC and Tumor Heterogeneity
- Anaplastic Lymphoma Kinase in NSCLC
- Acne Inversa/Hidradenitis Suppurativa
Project Title
Comparative Analysis of Tumor Heterogeneity in Non-Small Cell Lung Cancer (NSCLC) by Phosphoproteomics and Next Generation Sequencing (NGS)
Project Description
Heterogeneity in tumors might have different faces. In general, the role of different clones and sub-clones in different areas of one tumor is discussed. However, different diagnostic test facing the protein level (e.g. immunohistochemistry/IHC) on the one hand and the DNA-lev- el (e.g. Fluorescence in-situ Hybridization/FISH) on the other hand might produce discrepant results. Is this tumor heterogeneity, as well? In a first step, we addressed this question focusing on the Anaplastic Lymphoma Kinase, a treatable target in Lung Cancer. Underlined by our Next Generation Sequencing (NGS) – data, discrepant results by means of IHC and FISH might be due to technical (methodological heterogeneity) or biological (proteogenomic heterogeneity) reasons. Within the next step, we broaden our view (going away from focusing one target only), as recent data based on NGS, described tumor heterogeneity on the genetic level by Whole Exome Sequencing. However, data on the proteomic level are missing so far. Thus, in this study, we investigate the intratumoral heterogeneity of Non-Small Cell Lung Cancer (NSCLC) on the (phospo)proteomic level in comparison with mutational profiles (NGS-based). Thereby, we focus on the question if future molecular NSCLC-diagnostics should consider (a) aspects of heterogeneity (e.g. biopsies of different tumor regions) and (b) functional relevance of certain mutations (e.g. further investigation on the proteomic level), as the molecular complexity of the mutational landscape is discussed as mechanisms of resistance in targeted (personalized) cancer therapy. In the clinical context (e.g. tumor board) our data might, in perspective, help to identify and predict therapy resistance, as well as propose alternative therapy options.
Dr. med. Niels von Wardenburg
Charité – Universitätsmedizin Berlin, Department of Neurology and Experimental Neurology
Email: niels.von-wardenburg@charite.de
Fields of Research
- Advanced Cell Therapy
- Neuroimmunology
- B-cell mediated Disorders
Project Title
Preclinical development of chimeric autoantibody receptor (CAAR) T cells for the treatment of Myasthenia gravis
Project Description
Myasthenia gravis (MG) is an autoantibody-mediated neuromuscular disorder with generalized or localized weakness of skeletal muscles (1). In about 80% of all cases, autoantibodies directed to the nicotinic acetylcholine receptor (nAChR, in the following referred to as AChR) are present, causing receptor internalization, blockade and complement activation (2). Chimeric antigen receptor (CAR) T cells have been developed for the treatment of hematologic malignancies. An antibody fragment (scFv) expressed on the cell surface of T cells confers detection of tumor cells. Intracellular activation (e.g. CD3z) and co-stimulatory domains (e.g. CD137) of the CAR mediate T cell activation and cytolysis of respective target cells (3). The striking therapeutic success in treating refractory B cell malignancies has led to admission of Tisagenlecleucel (Kymria®) by the US Food and Drug Administration (FDA) in 2017. In our approach, we engineer chimeric autoantibody receptor (CAAR) T cells that deplete specifically AChR-reactive B cells, which express anti-AChR autoantibodies as B cell receptors on their cell surface. A CAAR resembles the CAR in design and functionality, but the scFv is replaced by the autoantigen’s ectodomain, thereby enabling the detection of anti-AChR B cells.
Dr. med. Tu-Lan Vu-Han, PhD
Charité – Universitätsmedizin Berlin, Center for Musculoskeletal Surgery
Email: Tu-lan.vu-han@charite.de
Fields of Research
- Drug Targeting Epigenetic Regulators
- Early Onset and Neuromuscular Scoliosis
- 5q-Spinal Muscular Atrophy
Project Title
ML-based Prediction of Scoliosis in SMA in Response to Novel Therapies
Project Description
5q-spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by the biallelic loss of the SMN1 gene. The absence of SMN1 transcripts leads to an SMN protein deficiency that causes progressive degeneration of anterior motor neurons and muscular atrophy. Patients with severe forms of disease manifestation often lack sufficient copy numbers of the gene paralog SMN2, which also encodes for the full-length SMN protein, but is truncated and rendered functionless through an alternative splicing mechanism.
Groundbreaking research throughout the past three decades has provided us with insights into the molecular genetic basis of SMA. These insights have fueled drug development to treat the underlying cause of this devastating disease: In 2017, the first FDA-approved antisense-oligonucleotide, splice-modification therapy nusinersen Spinraza® became available, which promotes the full-length transcription of SMN from available SMN2 genes. In 2019 the first gene replacement therapy arrived, onasemnogen Zolgensma®, which utilizes the AAV9 platform for delivery of SMN1 cDNA. In 2020, the first oral splice modification therapy, risdiplam Evrysdi®, followed.
SMA therapies have shown promising outcomes in increasing survival and improving motor functions in SMA patients. Thus, in December 2020, the Gemeinsamer Bundesausschuss (G-BA) approved the implementation of SMA in extended newborn screening programs, which will take a Germany-wide effect in October 2021.
Researchers, as well as medical practitioners, expect the efficacy of these novel therapies to change the natural history of the patient phenotype. As a result, many disciplines will require updated treatment standards and strategies for SMA-associated sequelae, of which the SMA-associated scoliosis is an essential one.
The objective of this project is to use a Machine Learning approach to predict SMA-associated scoliosis development in response to novel SMA therapies. Our ultimate goal is to provide a helper tool that will help physicians and surgeons in their decision-making during treatment optimization for SMA patients.Katharina Wansch
Charité-Universitätsmedizin Berlin, Medizinische Klinik m. S. Hämatologie, Onkologie und Tumorimmunologie (CCM)
Email: katharina.wansch@charite.de
Fields of Research
- Translational oncology
- Organoids
- Gastroenterology
Project Title
Mechanisms of acquired chemotherapy resistance in pancreatic ductal adenocarcinoma in organoid models
Project Description
Pancreatic cancer represents one of the deadliest types of cancers with an overall survival rate of 10%. Effective treatment options are limited since pancreatic cancer shows high levels of chemotherapy resistance. Furthermore, no clinically established biomarkers have been determined for predicting the individual chemotherapeutic response of patients. As surgery represents the only curative treatment option of pancreatic cancer, effective adjuvant chemotherapy remains crucial. The high chemoresistance and ineffective treatment options, however, lead to relapse rates of up to 80%.
In recent years, organoid technology has provided a promising platform for studying the tumor physiology of pancreatic cancer. These models can be established from tumor tissue and used for functional analyses, which allows individual prediction platforms to be developed. Up until today, however, organoid models have been used to evaluate drug responses at a single time point only. For a better understanding to be gained, this project aims at developing a dynamic predictive platform as well as understanding the dynamic changes in chemotherapeutic resistance.
In the first part of the project, 10 patient-derived organoid cultures from treatment-naïve patients will be established and characterized by histology, immunohistochemistry, genomic sequencing and treatment response. To induce chemoresistance, the cultures will be exposed to several cycles of chemotherapy using the same regimens as in the clinic. We will identify mechanisms of resistance on a functional level by analyzing the transcriptome and proteome of the organoids before, during and after the chemotherapy. Moreover, a comparison to the clinical data of the patients will be made.
Whether individual cell clones possess an intrinsically resistant or an acquired resistant phenotype when exposed to chemotherapy, is yet to be determined. To differentiate mechanisms of clonal selection, single-cell organoids will be developed. These organoids allow the identification of primary resistant clones within the heterogeneous treatment-naïve tumor cell population.
In conclusion, our research project aims at developing a dynamic predictive platform for chemotherapy resistance in pancreatic cancer. This way, mechanisms of resistance can be identified and personalized drugs identified. In the long term, high-throughput drug screening in dynamic predictive platforms may allow future advances in pancreatic cancer treatment.Dr. med. Carl Weidinger
Charité – Universitätsmedizin Berlin, Medical Department, Division of Gastroenterology, Infectiology and Rheumatology
Email: carl.weidinger@charite.de
Fields of Research
- Immunology Metabolism
- Oncology
Project Title
The Role of Mesenteric Fat in Intestinal Inflammation
Project Description
Creeping fat represents a disease characterizing finding in Crohn’s disease (CD) but its impact on intestinal inflammation and epithelial barrier function is unknown. Previous data indicate that bacterial translocation induces a unique immunologic and endocrine milieu within the mesenteric fat of CD patients resulting in immune cell infiltration as well as production of specific cytokines and adipokines thereby influencing intestinal inflammation. The present project aims to define how intestinal barrier defects shape the homeostasis of mesenteric fat, how these alterations confer to an alternative intestinal barrier and how creeping fat modulates epithelial resistance as well as intestinal immune cell composition and immunity. A fat-depleting mouse model will serve to answer these questions and the data will subsequently be correlated with results obtained from a CD patient cohort as well as from a patient with acquired generalized lipodystrophy and combined CD (AGLCD), who lacks mesenteric fat tissue and suffers from severe CD.
Dr. med. Carl Weidinger
Charité – Universitätsmedizin Berlin, Medical Department, Division of Gastroenterology, Infectiology and Rheumatology
Email: carl.weidinger@charite.de
Fields of Research
- Immunology Metabolism
- Oncology
Project Title
The Role of Mesenteric Fat in Intestinal Inflammation
Project Description
Creeping fat represents a disease characterizing finding in Crohn’s disease (CD) but its impact on intestinal inflammation and epithelial barrier function is unknown. Previous data indicate that bacterial translocation induces a unique immunologic and endocrine milieu within the mesenteric fat of CD patients resulting in immune cell infiltration as well as production of specific cytokines and adipokines thereby influencing intestinal inflammation. The present project aims to define how intestinal barrier defects shape the homeostasis of mesenteric fat, how these alterations confer to an alternative intestinal barrier and how creeping fat modulates epithelial resistance as well as intestinal immune cell composition and immunity. A fat-depleting mouse model will serve to answer these questions and the data will subsequently be correlated with results obtained from a CD patient cohort as well as from a patient with acquired generalized lipodystrophy and combined CD (AGLCD), who lacks mesenteric fat tissue and suffers from severe CD.
Dr. med. Veith-Andreas Weilnhammer
Charité – Universitätsmedizin Berlin, Department of Psychiatry and Psychotherapy
Email: veith‐andreas.weilnhammer@charite.de
Fields of Research
- Bayesian Modelling
- Computational Psychiatry
- fMRI
Project Title
The Influence of Expectations on Perceptual Decision in Patients with Paranoid Schizophrenia and Healthy Controls
Project Description
Bayesian brain theories posit that our central nervous system entertains a generative model to make inferences regarding the causes of the noisy and sparse information we receive through our senses. In this, perceptual decisions are thought to be based on posterior probability distributions, which are shaped by incoming sensory data and predictions about the dynamics and hierarchy of the environmental causes underlying such sensory data. Crucially, differences between predictions and sensory information are believed to represent so-called prediction errors, which serve to update the generative model represented by our central nervous system. Dopaminergic neurotransmission is thought to be crucial for this optimization procedure by adjusting the balance between incoming sensory information and prior knowledge for the process of perceptual decision-making. A shift in this balance has been discussed as a pathophysiological model for paranoid schizophrenia: Some authors hypothesize that perceptual decisions are distorted by overly strong predictions in paranoid schizophrenia. Others, however, argue for an enhanced impact of sensory information as the reason for perceptual abnormalities in this disease. In this project, we use behavioral modeling and model-based functional magnetic resonance imaging (fMRI) using bistable stimuli to study these processes in patients with paranoid schizophrenia and healthy controls. During my funding as a Junior Clinician Scientist, I published two fMRI studies on the role of prior predictions and prediction errors on perceptual processes during bistable perception in healthy observers: »A predictive coding account of bistable perception-a model-based fMRI study« (Plos Computational Biology, 2017) and »The Neural Correlates of Hierarchical Predictions for Perceptual Decisions« (Journal of Neurosci- ence, 2018). We are currently conducting a behavioral and fMRI experiment comparing patients with paranoid schizophrenia with healthy controls in a similar paradigm.
Dr. med. Veith-Andreas Weilnhammer
Charité – Universitätsmedizin Berlin, Department of Psychiatry and Psychotherapy
Email: veith‐andreas.weilnhammer@charite.de
Fields of Research
- Bayesian Modelling
- Computational Psychiatry
- fMRI
Project Title
The Influence of Expectations on Perceptual Decision in Patients with Paranoid Schizophrenia and Healthy Controls
Project Description
Bayesian brain theories posit that our central nervous system entertains a generative model to make inferences regarding the causes of the noisy and sparse information we receive through our senses. In this, perceptual decisions are thought to be based on posterior probability distributions, which are shaped by incoming sensory data and predictions about the dynamics and hierarchy of the environmental causes underlying such sensory data. Crucially, differences between predictions and sensory information are believed to represent so-called prediction errors, which serve to update the generative model represented by our central nervous system. Dopaminergic neurotransmission is thought to be crucial for this optimization procedure by adjusting the balance between incoming sensory information and prior knowledge for the process of perceptual decision-making. A shift in this balance has been discussed as a pathophysiological model for paranoid schizophrenia: Some authors hypothesize that perceptual decisions are distorted by overly strong predictions in paranoid schizophrenia. Others, however, argue for an enhanced impact of sensory information as the reason for perceptual abnormalities in this disease. In this project, we use behavioral modeling and model-based functional magnetic resonance imaging (fMRI) using bistable stimuli to study these processes in patients with paranoid schizophrenia and healthy controls. During my funding as a Junior Clinician Scientist, I published two fMRI studies on the role of prior predictions and prediction errors on perceptual processes during bistable perception in healthy observers: »A predictive coding account of bistable perception-a model-based fMRI study« (Plos Computational Biology, 2017) and »The Neural Correlates of Hierarchical Predictions for Perceptual Decisions« (Journal of Neurosci- ence, 2018). We are currently conducting a behavioral and fMRI experiment comparing patients with paranoid schizophrenia with healthy controls in a similar paradigm.
Dr. med. Julian Weingärtner
Charité – Universitätsmedizin Berlin, Department of Radiation Oncology and Radiotherapy
Email: julian.weingaertner@charite.de
Fields of Research
- Oncology
- Machine Learning
- Artificial Intelligence
Project Title
Artificial intelligence in functional imaging for individualized treatment of HNSCC patients
Project Description
Head and neck squamous cell carcinoma (HNSCC) represent the sixth most common cancer worldwide. The two curative treatment modalities for patients with HNSCC - primary chemoradiation (CRT) or primary surgery (often combined with postoperative (C)RT) - are both associated with serious side effects. Therefore, further stratification, optimization and personalization of treatment is urgently needed. As novel quantitative image analyses are a promising tool for further risk stratification, we´re training a three-dimensional Convolutional Neural Network on 18F-Fluorodesoxyglucose (FDG) positron emission tomography (PET) imaging and clinical / histopathological data of a multicentric, retrospective cohort of 1200 patients treated with primary CRT and 800 patients treated with primary surgery at Charité and cooperation institutes in order to predict individual treatment-specific outcomes and identify patients with excellent outcome after primary CRT or primary surgery or unfavorable outcome by both. The trained algorithm of the artificial intelligence will be validated in a prospective trial to see if predicted loco-regional control and recommended treatment strategies are reliable. In total 250 curative HNSCC patients, treated with CRT or primary surgery, will be enrolled on this prospective validation trial with observational character, while biomarker, clinical and FDG-PET data are collected from these patients and follow-up visits concluded.
Dr. med. univ. MSc. Nikolaus Wenger, PhD
Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology
Email: nikolaus.wenger@charite.de
Fields of Research
- Motor Recovery
- Neuroprosthetics
- Stroke Research
Project Title
Inducible Neuroplasticity after Stroke using Neurotransmitter Replacement Strategies
Project Description
Translating the behavioral output of the nervous system into movement involves interaction between the brain and the spinal cord. The brainstem provides an essential bridge between these two structures. However, the function of this intermediary system in motor recovery after stroke remains poorly understood. In fact, the brainstem is a major source of monoaminergic neurotransmitters that coordinate movement at the level of the spinal cord (Wenger et al. 2016) and mediate plasticity in the central nervous system (Ng et.al 2015). My hypothesis is that motor cortex stroke alters the activity of monoaminergic brainstem nuclei limiting functional recovery after stroke. Using neural tracing experiments and behavioral analysis, I aim to investigate the therapeutic effect of monoaminergic neurotransmitter replacement strategies to engage plasticity of neural networks related to motor production. The translational aim of this project is to investigate neuroanatomical rewiring processes that benefit the restoration of function after stroke.
Dr. med. Nicolas Wieder
Charité – Universitätsmedizin Berlin, Department of Neurology and Experimental Neurology
Email: nicolas.wieder@charite.de
Fields of Research
- Alzheimer's Disease
Project Title
Identifying Alzheimer’s Disease-Relevant Genes at the Intersection of Genomic Risk and Neuronal Lipotoxicity
Project Description
Complex diseases are caused by an interaction of genetic and environmental risk factors. Large-scale sequencing projects (genome wide association studies, GWAS) continue to illuminate the genetic architecture of complex diseases such as type 2 diabetes (T2D) and Alzheimer’s disease (AD); however, it remains challenging to connect the vast number of emerging disease-associated single nucleotide polymorphisms (SNPs) to cellular disease mechanisms. There is a need for systematic strategies that prioritize relevant genes of interest by accounting for environmental risk, especially given scenarios where genetic risk factors are often only revealed by an environmental trigger. An important environmental trigger for a whole array of complex disease including, but not limited to, T2D, coronary artery disease and AD is the overabundance of dietary lipids, predominately in the form of triglycerides (TAGs). This leads to the accumulation of free fatty acids (FFAs) in various tissues, inducing a detrimental cellular state known as lipotoxicity. To date, there is no comprehensive understanding of the contribution across the full spectrum of structurally heterogenous FFAs to disease pathogenesis. AD is one of the most prevalent complex neurological disorders of our time and the contribution of lipids, and FFAs in particular, to disease progression has been recognized before. The identification of the ɛ4 allele of apolipoprotein E (APOE) gene as the most significant genetic risk factor for AD strongly supports these observations. To specifically address the question how environmentally driven exposure to certain lipids interacts with the genomic risk for AD, we will integrate publicly available GWAS datasets for AD with a novel, transcriptionally derived signature of lipotoxicity in neurons, the primarily implicated neuronal cell type in AD. More specifically, we will expose iPSC derived neurons to a library of 61 biologically relevant but structurally diverse FFAs and perform transcriptomics for each of them. The resulting, unbiased signature of lipotoxicity will then be overlaid with genes ranked by their proximity to SNPs resulting from GWAS for AD. We expect the integration of these two orthogonal lines of evidence to reveal disease relevant genes at the intersection of environmental and genomic risk for AD that constitute prime candidates for further validation studies to investigate their potential as novel drug targets.
Dr. med. Nicola Wilck
Charité – Universitätsmedizin Berlin, Medical Department, Division of Nephrology and Internal Intensive Care Medicine
Email: nicola.wilck@charite.de
Fields of Research
- Inflammation in Cardiovascular Disease
- Intestinal Microbiome
- Host‐Microbiome Interaction
Project Title
Putative Role for Bacterial Metabolites in Protection from Hypertensive Organ Damage
Project Description
Hypertension and subsequent damage to the heart and kidneys contribute to cardiovascular morbidity. Besides hemodynamic stress, an important role for the immune system has been uncovered, linking pro-inflammatory T effector cells to the development of hypertension. In particular, interleukin-17A producing TH17 cells promote hypertension and organ damage. Although the deleterious role of inflammation in hypertension has been recognized, current treatments insufficiently address these mechanisms. This project aims to elucidate the role of tryptophan metabolites of bacterial origin in hypertensive renal and cardiac damage. It is based on the recognition that gut bacteria affect host organs and the immune system by virtue of their metabolites. Tryptophan is metabolized by intestinal bacteria to indoles. We have shown that a probiotic Lactobacillus treatment reduces blood pressure and provides beneficial immunomodulation in experimental hypertension, putatively via production of indoles. This project aims to expand on these observations by using cell culture systems, a rat model as well as patient material. Candidate indoles selected in vitro as well as probiotic treatments will be tested for their immunomodulatory and organ-protective potential in hypertensive double-transgenic rats. Tryptophan metabolite analysis will be performed in hypertensive patients, potentially enabling future translation.
Jason Witte
Charité-Universitätsmedizin Berlin, Julius Wolff Institut für Biomechanik und Muskulosksletale Regeneration (BIH)
Email: jason.witte@charite.de
Fields of Research
- Molecular Traumatology
- Fracture healing
- Chronobiology
Project Title
Impact of the circadian clock on fracture healing in murine Bmal1 knockout model
Project Description
The circadian clock controls fundamental physiological processes such as body temperature, metabolic activity, hormonal balance and also bone remodeling. Dysfunction of the biological clock, as observed in rotating shift work or sleep disturbances, has been shown to affect the bone structure in patients and animal models. However, the role of the circadian clock in fracture healing is still completely unknown. To explore this, we used a genetically modified murine Bmal1 knockout model and induced a femoral osteotomy. The movement analysis of Bmal1-deficient mice revealed an arrhythmic activity under 12-hour light-dark conditions as well as in constant darkness. These mice exhibited lower callus volume on micro-CT analysis 7, 14, and 21 days after osteotomy compared to their wild-type littermates, which retained a circadian rhythm even in constant darknes. In addition, histologic analysis of the fracture callus revealed decreased callus growth and deteriorated bridging of the fracture gap after 7, 14 and 21 days in arrhythmic mice, with both osteoblasts and osteoclasts decreased. Thus, with this study, we demonstrated for the first time, that Bmal1, as a major element of the circadian clock, is essential for bone healing. This suggests, that disturbances of this rhythm may also negatively effect healing in human patients.
Dr. med. Jonas Wizenty
Charité – Universitätsmedizin Berlin, Department of Hepatology and Gastroenterology
Email: jonas.wizenty@charite.de
Fields of Research
- Gastrointestinal Barrier, Regeneration and Carcinogenesis
- Tissue Microbiology
- Stem Cell Biology
Project Title
Inflammatory Mechanisms of Gastric Stem Cells Upon Infection
Project Description
Mechanisms by which mucosal surfaces discriminate between harmless bacteria and pathogens are not well understood. Helicobacter pylori colonizes the stomach of about 50% of the world´s population and is the main risk factor for gastric cancer. A subpopulation of gland-associated bacteria, in contrast to bacteria found on the surface, induces an inflammatory response, which leads to chronic gastritis as well as gland hyperplasia and metaplasia, which are precursor lesions for gastric cancer. To maintain gland homeostasis, a close interplay between epithelial and stromal cells builds a molecular signaling network that controls epithelial turnover and differentiation. The gastric gland base contains gastric stem cells that are characterized by high Wnt signaling and expression of stem cell markers such as Axin2 and Lgr5. This cell population relies on stromal-derived R-spondin. Using in vivo mouse models, in which the stem cell compartment can be altered, and the organoid culture system, we will demonstrate that gland base stem cells function as important sensors and effectors of bacterial infections and establish a novel link between stem cell signaling and mucosal immunity. Mechanistically, the interplay between R-spondin and NF-κB signaling and their impact on epithelial homeostasis, inflammation and infection will be explored.
PD Dr. med. Tobias Wollersheim
Charité – Universitätsmedizin Berlin, Department of Anesthesiology and Operative Intensive Care Medicine
Email: tobias.wollersheim@charite.de
Fields of Research
- Pathophysiology and Preventive Strategies of Neuromuscular Organ Failure in Critically ill Patients
- Metabolism in Critically ill Patients
Project Title
Prevention of Neuromuscular Organ Failure in Critically ill Patients
Project Description
My research focus as a Clinician Scientist is the prevention of ICU-acquired muscle weakness via advanced, muscle activating physiotherapy methods. The current therapeutic options allow for the survival of severe diseases. Serious neuromuscular sequelae are an increasing problem that significantly worsens the acute and long-term outcomes in terms of reduced physical functional, reduced quality of life, and increased mortality. We have shown that systemic inflammation and immobilization are major risk factors, inducing pathophysiological processes that lead to an ICU-acquired weakness. Decreased protein synthesis, increased protein degradation, and metabolic dysregulation in the form of a pronounced insulin resistance are detected very early in the course of critical illness. We could recently show that a daily exercise program with electric muscle stimulation can maintain muscle mass, as well as improve glucose metabolism in skeletal muscle. However, these successes are inconsistent and patient-specific, so that a broad application is not yet recommended. From the data of earlier investigations, we could determine the key factors influencing the effectiveness of enhanced physiotherapy options in the prevention of neuromuscular organ failure. Considering these findings, a specific therapy will be further developed under standardized conditions using an established sepsis-mouse-model. Furthermore, recent investigations lead us to the point that neuromuscular failure already occurs during perioperative setting. Therefore, we just initiated an observational trial to confirm these findings of the first description of Perioperative Acquired Weakness (POAW). My work is embedded within the BIH Twinning Research Grant project »Inflammation-induced skeletal muscle atrophy in critically ill patients«. Additional research interests: glucose metabolism, glucose monitoring, insulin therapy, nutritional support, caloric needs, indirect calorimetry, extracorporeal membrane oxygenation.
Dr. med. Hannah Woopen, MSc
Charité – Universitätsmedizin Berlin, Department of Gynecology
Email: hannah.woopen@charite.de
Fields of Research
- Polypharmacy in Ovarian Cancer
- Supportive Care in Ovarian Cancer
- Longterm Survival with Ovarian Cancer
Project Title
Caroline Meets HANNA - Holistic Analysis of LoNgterm-Survivors with OvariaN CAncer
Project Description
Ovarian cancer is the leading cause of mortality of all gynecological cancers. Despite radical surgery followed by adjuvant platinum-based chemotherapy 75-80% of patients relapse within the first years after chemotherapy and die from the disease. However, there is a rare patient group who survives longer than eight years after initial diagnosis, sometimes even despite several recurrences of the disease. Typical prognostic factors such as age, FIGO stage, and tumor residuals after cytoreductive surgery cannot completely explain this phenomenon. The aim of this study is to identify factors that are unique in longterm-survivors regarding tumor biology, immunological features, resilience and clinical factors such as comedication, polypharmacy, and comorbidities. Furthermore, we are investigating lifestyle factors such as nutrition, physical activity, and sleep quality. Our results shall
have an impact on survival of our ovarian cancer patients – also by factors that patients can modify by them- selves. The project name is based on the patrons of this study: Mrs. Caroline Masur, who was diagnosed with ovarian carcinoma more than ten years ago and still experienced no relapse. As well as on Hanna, a Catholic nun, who survived the disease despite a relapse for more than eight years. More information can be found at: www.carolinmeetshanna.comDr. med. Thomas Heinrich Wurster
Charité – Universitätsmedizin Berlin, Department of Cardiology
Email: thomas‐heinrich.wurster@charite.de
Fields of Research
- Cardiovascular Imaging
- Positron Emission Tomography/ Magnetic Resonance (Imaging)
Project Title
Molecular PET/MR-Imaging in Coronary Artery Disease
Project Description
Atherosclerotic plaque rupture in coronary arteries can lead to myocardial infarction and in some cases to sud- den cardiac arrest. Plaques prone to rupture are considered as »vulnerable plaques« and feature distinct characteristics, such as a large necrotic core covered by a thin fibrous cap, macrophage, and positive vascular re- modeling. A substantial number of these «high-risk lesions« do not cause flow-limiting stenosis and therefore can detract from common non-invasive diagnostic stress testing and invasive x-ray coronary angiography. Intravascular imaging techniques, such as intravascular ultrasound (IVUS) and optical coherence tomography (OCT) demonstrated great potential in the assessment of plaque morphology. However, the application is limited due to invasiveness. Cardiac magnetic resonance imaging (MRI) on the other hand is a non-invasive imaging modality that provides excellent soft-tissue contrast. CMR assessment of atherosclerotic altered coronary arteries can depict plaque burden and plaque composition. Positron Emission Tomography (PET), usually combined with computed tomography (PET/CT) for anatomical detail, is a non-invasive imaging modality, which provides molecular information. Dependent on the tracer used, specific pathological processes, such as micro-calcification (18F-fluoride) can be studied. Recently developed PET/MR scanners with the opportunity of simultaneous assessment of structure and biology offer great potential in cardiovascular imaging. The aim of our project is to evaluate the potential of PET/MR imaging in coronary artery disease.
Dr. med. Ran Xu
Charité – Universitätsmedizin Berlin, Department of Neurosurgery
Email: ran.xu@charite.de
Fields of Research
- Subarachnoid hemorrhage (SAH)
- extracellular RNA
- brain-heart axis
Project Title
Microglia-Associated Inflammation after Subarachnoid Hemorrhage (SAH)
Project Description
Subarachnoid hemorrhage (SAH), caused by the rupture of an intracranial aneurysm contributes for a third of all hemorrhagic strokes and is a devastating disease with a mortality of approx.. 25% and 40%. This pathology poses a unique role in hemorrhagic stroke, since it occurs outside the brain parenchyma at the base of the brain within the basal cisterns that then leads to intraparenchymal damage in an outside-in fashion. Previous studies from our laboratory have shown that microglia accumulation and activation within the brain induces neuronal cell death after experimental subarachnoid hemorrhage, which in turn may contribute to secondary brain injury. This project aims at further characterizing the functional phenotype of resident CNS-macrophages/microglia, and
studying their association with the pathological hallmarks of secondary cellular brain injury following SAH in an animal model (fi lament perforation model). MRI in vivo and ex vivo studies are undertaken to confirm the bleeding and study imaging patterns of SAH. Microglia cells are isolated for RNASeq studies, and further immunofluorescence studies and behavior studies are performed to dissect the dynamics within the course of SAH. In parallel, blood and CSF samples from SAH patients are collected in a prospective study which will be analyzed for potential targets of the immune system.Dr. med. Kun Zhang
Charité – Universitätsmedizin Berlin, Department of Cardiology
Email: kun.zhang@charite.de
Fields of Research
- Calcium Signaling in Heart Failure
- Excitation‐Secretion Coupling in Cardiomyocytes
Project Title
The Heart as an Endocrine Organ: Chromogranin B and the Inositol-1,4,5-Trisphosphate Receptor in Excitation-Secretion Coupling in Cardiomyocytes
Project Description
In endocrine cells, a crucial role of chromoganin B (CGB) and the inositol-1,4,5-trisphosphate receptor (IP3R) in exocytosis of vesicles and hormone secretion is known. The heart owns characteristics of an endocrine organ as well. We could show that CGB as a marker of secretory granules is also expressed in cardiomyocytes and demonstrated a pathophysiological pathway of the CGB and IP3R interaction in cardiac hypertrophy and heart failure. While excitation-secretion coupling is well described in other excitable cells such as neurons, this concept is novel and not yet studied in cardiomyocytes. Aim of this project is to examine the functional role of CGB and the IP3R in excitation-secretion coupling in cardiomyocytes and in murine models of heart failure with preserved ejection fraction (HFpEF). Final goal will be to establish a pathway that can serve as a new target in heart failure treatment.
Dr. med. Jörn Felix Ziegler
Charité – Universitätsmedizin Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology
Email: joern-felix.ziegler@charite.de
Fields of Research
- Inflammtory Bowel Disease
- Adipose Tissue
- Epithelial Cells
Project Title
Fat Signals - Characterizing the influence of mesenteric adipose tissue on intestinal epithelium in Crohn’s disease
Project Description
Mesenteric adipose tissue is actively involved in the regulation of various physiologic and pathophysiologic processes, including inflammatory bowel disease and here in particular small intestinal Crohn’s disease. In this group of patients, mesenteric adipose tissue is characterized by a unique behavior, also known as “creeping fat”: Hyperplastic mesenteric adipose tissue wraps around inflamed small intestinal segments. Accordingly, extensive research has been performed on interactions with the immune system, e.g., demonstrating immunomodulatory properties of secreted adipokines like leptin and adiponectin. Other data indicate that creeping fat is a reaction to and barrier against translocation of microorganisms. Studies investigating potential interactions of creeping fat and intestinal epithelial cells are, however, sparse, use cell lines and animal models with their respective limitations and often focus on specific adipokines. In this project, we therefore aim to elucidate the effects of mesenteric adipose tissue-derived soluble factors on the intestinal epithelium in more depth. In order to use a model that can mimic in-vivo physiology and 3D architecture more closely, we employ patient-derived primary human intestinal organoids to characterize the effects of soluble factors from mesenteric adipose tissue of Crohn’s disease patients and controls. Thereby we want to enhance our understanding of creeping fat’s role in the pathogenesis of Crohn’s disease and hope to identify potential novel therapeutic targets.
Dr. med. Felix Zirngibl
Charité – Universitätsmedizin Berlin, Department of Pediatrics, Division of Oncology and Hematology
Email: felix.zirngibl@charite.de
Fields of Research
- Immunooncology
- Bispecific Trifunctional Antibodies
- Neuroblastoma
Project Title
Functional and Therapeutic Evaluation of a Trifunctional Bispecific Antibody Against Neuroblastoma
Project Description
Neuroblastoma is the most common solid tumor of childhood. Approximately 50% of all children initially present with a high-risk disease, for which therapeutic options are extremely aggressive and have limited cure rates. Of the high-risk patients treated in Germany between 1990 and 2007, 56% relapsed. Only very limited therapeutic options exist for relapsed neuroblastoma, and 5-year survival is < 10% in patients. New therapeutic options are needed to improve cure rates for patients with refractory or relapsed neuroblastoma. Immunotherapies with monoclonal antibodies are gaining more importance for oncology. Treatment with the ch14.18 antibody was recently reported to improve 2-year survival in patients with high-risk neuroblastoma by 20%. Trifunctional bispecific antibodies destroy tumor cells and prevent relapse by combining direct tumor lysis via simultaneous tumor and effector cell binding with a long-term vaccination. A trifunctional bispecific antibody has shown promising preclinical results in mouse models for malignant melanoma. Tumor cells can circumvent the host immune system by expressing surface proteins that interact with T cells, which immune checkpoint inhibitors block, to avert this escape mechanism. Through combining trifunctional bispecific antibodies with checkpoint inhibitors, we aim to both enhance the direct cytotoxic effect and achieve tumor vaccination. The proposed project will preclinically evaluate (i) the efficacy of trifunctional bispecific antibodies directed against the neuroblastoma-specific marker, GD2, in vitro and in vivo and (ii) the effectiveness of combining this type of immunotherapy with checkpoint inhibitors. These necessary preclinical data will help develop a trial protocol for patients with refractory or relapsed neuroblastoma. Our long- term aim is to improve survival of children diagnosed with high-risk neuroblastoma.
PD Dr. med. Sebastian Zschaeck
Charité – Universitätsmedizin Berlin, Department of Radiation Oncology and Radiotherapy
Email: sebastian.zschaeck@charite.de
Fields of Research
- Functional Imaging
- Normal Tissue Effects of Radiotherapy
- Tumor Hypoxia
Project Title
Characterization of the Tumor and its Surrounding Microenvironment During Treatment to Improve Future Cancer Therapies
Project Description
Radiation therapy combined with chemotherapy (CRT) is the standard of care for locally advanced head and neck squamous cell cancer (HNSCC) and as a preoperative or definitive treatment for esophageal squamous cell carcinoma (ESCC) patients. Metabolic imaging using 18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) is commonly used for staging and re-staging in these patients but the imaging information is not yet routinely used to provide additional prognostic or predictive information during treatment. Therapy-induced FDG uptake of tumor surrounding irradiated normal tissue (INT) has been shown to have a high prognostic impact in both diseases. Additionally, INT cutoff values generated in hypothesis-generating cohorts were able to discriminate patients at high or low risk for local recurrence and death in independent HNSCC and ESCC validation cohorts. When using additional imaging tracers INT showed a strong inverse correlation with tumor hypoxia. Hypoxia is a known adverse prognostic factor in almost all solid tumors, promoting chemo- and radio-resistance and metastasis. The underlying biological mechanisms for the association of INT with patient outcome and tumor hypoxia remain unclear so far. The aim of this research project is to validate INT in combination with tumor parameters in a prospective cohort of ESCC patients undergoing CRT and unravel the biological underpinnings of this phenomenon. For the latter, one patient will receive functional imaging together with analyses of radiation-induced immune response in HNSCC and additionally cell culture of a primary tumor, mucosa and immune cells in ESCC patients. mRNA NanoString analyses will be performed in the already evaluated HNSCC and ESCC cohorts with the aim to identify candidate genes for consecutive cell co-culture experiments.