Fellows und Alumni der BIA Clinician Scientist Programme


PD Dr. med. Güliz Acker

Charité – Universitätsmedizin Berlin, Department of Neurosurgery with Pediatric Neurosurgery


gueliz.acker@charite.de

    Fields of Research

  • Moyamoya Disease
  • Glioblastoma Multiforme
  • Vascular Targeting
Details

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 glio- blastoma 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.

Dr. med. Lisa Adams

Charité – Universitätsmedizin Berlin, Department of Radiology

Charitéplatz 1, 10117 Berlin,


lisa.adams@charite.de

    Fields of Research

  • Molecular Imaging
  • Aortic Aneurysms
  • Quantitative MR Imaging
Details

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
Details

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. Judith Altmann

    Fields of Research

  • Preeclampsia
  • Oocyte-donation pregnancies
  • Perinatal Medicine
  • Obstetrics
Details

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. Martin Atta Mensah

Charité – Universitätsmedizin Berlin, Institute of Medical Genetics and Human Genetics


martin‐atta.mensah@charite.de

    Fields of Research

  • Exomics
  • Syndromology
  • Computer‐Aided Photogrammetry
Details

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

Details

Dr. med. Magdalena Balcerek

Charité – Universitätsmedizin Berlin, Department of Pediatrics, Division of Oncology and Hematology


magdalena.balcerek@charite.de

    Fields of Research

  • Paediatric Oncology and Haematology
  • Fertility Impairment
  • Quality of Life
Details

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. Francis Baumgartner

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Dr. med. Nikolaus Behr

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Dr. med. Sabine Bélard, MSc, DTM&H

Charité – Universitätsmedizin Berlin, Department of Pediatrics, Division of Pneumonology and Immunology


sabine.belard@charite.de

    Fields of Research

  • Tuberculosis
  • Tropical Medicine
  • Infectious Diseases
Details

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

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Dr. med. An Bin Cho

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Dr. med. Philip Bischoff

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Dr. med. Elisabeth Blüthner

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Dr. med. Tim Bastian Brämswig

Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology


tim‐bastian.braemswig@charite.de

    Fields of Research

  • Silent Brain Infarcts
  • Cerebral Imaging in Stroke
Details

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.

Dr. med. Katarina Braune

Charité – Universitätsmedizin Berlin, Department of Pediatrics, Division of Endocrinology and Diabetology


katarina.braune@charite.de

    Fields of Research

  • Telemedicine
  • Big Data
  • Value‐Based Health Care
Details

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.

Dr. med. Keno Bressem

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Dr. med. Ana Luisa de Almeida Marcellino

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Dr. med. Uta Margareta Demel

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Dr. med. Jan Rafael Dörr

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Dr. med. Julius Emmrich


julius.emmrich@charite.de

Details

Project Title

Mechanisms of Neuronal Dysfunction and Death in Sepsis-associated Cognitive Impairment

Project Description

There is compelling evidence that survivors of critical illness that enter medical care with no evidence of cognitive impairment are often discharged with severe de novo neurocognitive decline that is long-lasting and likely permanent. More than one in three patients have profound cognitive impairments for at least one year after release from an intensive care unit (ICU) and as medical care is improving and the number of ICU admissions is increasing worldwide, the number of survivors of critical illness is growing.
Sepsis, a potentially life-threatening systemic inflammation, is a leading cause of ICU admission and commonly precipitates severe long-term cognitive impairment. Recent studies aiming to elucidate the neuronal correlate of cognitive demise have found neuroinflammation (i.e. activation of microglia, the immune cells of the central nervous system), and neuronal death to be responsible for diffuse cerebral damage and eventually brain atrophy. However, the underlying pathophysiology remains poorly understood and there is no available treatment.
Microglial phagocytosis (i.e. engulfment and degradation of a target) is a crucial process to maintain brain homeostasis during injury as it prevents tissue damage resulting from leakage of toxic intracellular components from dying cells. Thus, it has previously been assumed that microglial phagocytosis of neurons is entirely beneficial and always preceded by a cell’s commitment to cell death. However, based on our recent observations indicating that microglia can engulf and thereby eliminate functional neurons and/or synapses during neuroinflammation, it is conceivable that neuronal and/or synaptic loss following sepsis is executed by microglial phagocytosis. The aim of this project is to investigate if phagocytosis of neurons and/or synapses is beneficial or detrimental for cognitive outcome following sepsis and this project will determine whether anti-phagocytic treatment may be a therapeutic option for preventing cognitive deficits in sepsis survivors.

Cornelius Engelmann

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Dr. med. Johannes Eschrich

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Dr. med. Philipp Euskirchen

Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology


philipp.euskirchen@charite.de

    Fields of Research

  • Neuro‐Oncology
  • Tumor Heterogeneity
  • Molecular Diagnostics
Details

Project Title

Molecular Mechanisms of Tumor-Immune Cell Interaction in Glioblastoma

Project Description

It has long been recognized that tumor-associated microglia and macrophages (TAMs) can account for 30% or more of tumor cells in glioblastoma (GBM), the most frequent primary brain tumor in adults with a dismal prognosis of about 15 months overall survival. Importantly, we have recently shown that the amount of non-tumor cells in GBM is a negative predictor of survival (Heuling et al., 2017). On the molecular level, a solid body of experimental evidence on the functional and molecular interactions between glioma and local innate immune cells convergently shows that microglia and macrophages support tumor growth in GBM. However, clinical trials of CSF1R inhibition to selectively deplete TAMs in GBM have failed. In addition, the high interindividual variability of immune infiltration across GBM remains largely unexplored. We have found strong associations between mutually exclusive key driver mutations and the amount of immune infiltration, which might explain the failure of clinical trials. The overall aim of this project is therefore to identify patients that will benefit from targeted therapy, gain mechanistic insights to establish causality and provide the diagnostic tools for patient-tailored precision oncology.

Dr. med. Mathilde Feist

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Dr. med. Matthaeus Felsenstein

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Dr. med. Florian Nima Fleckenstein

Charité – Universitätsmedizin Berlin, Department of Radiology


florian.fleckenstein@charite.de

    Fields of Research

  • Interventional Oncology
  • Quantitative MR Imaging
  • Machine Learning
Details

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. Carina Flemmig

Charité – Universitätsmedizin Berlin, Department of Pediatrics, Division of Oncology and Hematology


carina.flemmig@charite.de

Details

Project Title

Improving Immunotherapy in Neuroblastoma

Project Description

Children with relapsed or refractory neuroblastoma have a <10% survival chance with current treatment options. It is reported that survival is improved in neuroblastoma patients with elevated tumor infiltration by endogenous T-cells. Modified T-cell therapy has been highly successful against leukemias cells but is less effective against solid tumors. Low T-cell recruitment and an immunosuppressive tumor microenvironment are the main hurdles preventing success against solid tumor. We aim to further develop immunotherapeutic approaches for neuroblastoma by combining genetically modified T-cells (CAR and TCR) with targeted therapy, e.g. Smac mimetics. Targeted therapeutic compounds can activate NFκB signaling, which sequentially alters the tumor cytokine profile and microenvironment. We envisage that combining targeted therapeutic compounds with genetically modified T-cells will increase the migration and invasion of modified T-cells, thereby increasing the efficacy of adoptive T-cell therapy in refractory or relapsed neuroblastoma patients. The project is designed to first investigate the effects of Smac mimetics on the two players in the compartment where immunotherapy is active: the genetically modified T-cells and the tumor cells (including their impact on their microenvironment). Then we will then assess efficacy of combination treatment in a novel 3D culture model before testing promising targeted therapeutic compounds in mice. Our aim is to provide the necessary information obtained in in vitro and in vivo experiments to design a phase I/II clinical trial to test this immunotherapy in patients with refractory and relapsed neuroblastoma and learn more about the immune – tumor cell interactions to optimize adoptive T-cell therapy.

Dr. med. Julian Friebel

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Dr. med. Dr. phil. Eva Friedel

Charité – Universitätsmedizin Berlin, Department for Psychiatry and Psychotherapy


eva.friedel@charite.de

    Fields of Research

  • Learning and Cognition
  • Imaging Genetics and Epigenetics
  • Alcohol Use Disorder
Details

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


vivien.friedrich@charite.de

    Fields of Research

  • Brain Development
  • Oligodendroglia and Purkinje Cells
  • Hyperoxia
Details

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


steffen.fuchs@charite.de

    Fields of Research

  • Neuroblastoma
  • Gene Expression Regulation
  • Circular RNAs
Details

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.

Dr. med. Theresa Gerhardt

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Dr. med. Brigitta Globke

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Dr. med. Carl Christoph Goetzke

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Dr. med. Simon Gräber

Charité – Universitätsmedizin Berlin, Department of Pediatrics, Division of Pneumonology, Immunology


simon.graeber@charite.de

    Fields of Research

  • CFTR Biomarker
  • CFTR Modulator
  • Airway Hydration Therapies
Details

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. Julius Grunow

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Dr. med. Lea-Maxie Haag

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Dr. med. Stefan Habringer

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Dr. med. Rene Hägerling

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Univ.-Prof. Dr. med. Dr. rer. nat. Ahmed Nabil Hegazy

Charité – Universitätsmedizin Berlin, Medical Department, Division of Gastroenterology, Infectiology and Rheumatology


ahmed.hegazy@charite.de

    Fields of Research

  • Immunological Memory
  • Host‐Microbiota Interactions
  • Inflammatory Bowel Disease
Details

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

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Dr. med. Georg Hilfenhaus

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Dr. med. Karl Herbert Hillebrandt

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PD Dr. med. univ. Felix Hohendanner, PhD

Charité – Universitätsmedizin Berlin, Department of Cardiology


felix.hohendanner@charite.de

    Fields of Research

  • Experimental Cardiology
Details

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. Andreas Horn, MD, PhD

Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology


andreas.horn@charite.de

    Fields of Research

  • Deep Brain Stimulation
  • Movement Disorders
  • Brain Connectivity
Details

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.

Dr. med. Paul Jahnke

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Dr. med. Philipp Jurmeister

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Dr. med. Eva Käbisch

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Dr. Michael Kaczmarczyk

Charité – Universitätsmedizin Berlin, Department of Psychiatry


michael.kaczmarczyk@charite.de

    Fields of Research

  • Major Depressive Disorder
  • Neuroenhancement
Details

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.

Dr. med. Jakob Kaminski

Charité – Universitätsmedizin Berlin, Department of Psychiatry and Psychotherapy


jakob.kaminski@charite.de

    Fields of Research

  • Neuroscience
  • Cognition
  • Schizophrenia
Details

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. Marcus Kelm

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Dr. med. univ. Barbara Kern, PhD

Charité – Universitätsmedizin Berlin, Department of Surgery


barbara.kern@charite.de

    Fields of Research

  • Vascularized Composite Tissue
  • Allotransplantation
  • Transplant Immunology
Details

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 Khalil

Details

Dr. med. Evelyn Kidess-Sigal

Charité – Universitätsmedizin Berlin, Medical Department, Division of Hepatology and Gastroenterology


evelyn.kidess@charite.de

    Fields of Research

  • Circulating Tumor Cells
  • Circulating Tumor DNA
Details

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. Arne Kienzle

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Dr. med. Samuel Knauss

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Dr. med. Leif Torben Koschützke

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Dr. med. Matteus Krappitz

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Dr. med. Jana Krech

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Dr. med. Daniel Kroneberg

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Dr. med. Dorothee Kübler

Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology

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Dr. med. Joseph Kuchling

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Dr. med. Anna Kufner

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Dr. med. Gunnar Lachmann

Charité – Universitätsmedizin Berlin, Department of Anesthesiology and Operative Intensive Care Medicine


gunnar.lachmann@charite.de

    Fields of Research

  • Immune Function in Critically ill Patients
  • Immune Stimulation in Immune Suppression
  • Hemophagocytic Lymphohistiocytosis in ICU
Details

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

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Dr. med. Tina Mainka

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Dr. med. Jochen Michely

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Dr. med. Mirja Mittermaier

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Dr. rer. nat. Melba Muñoz Roldán, MSc

Charité – Universitätsmedizin Berlin, Department of Dermatology, Venerology and Allergology


melba.munoz‐roldan@charite.de

    Fields of Research

  • Mast Cells in Viral Infections
  • Inflammatory Skin Diseases
  • Novel Mast Cell and T‐cell Interactions
Details

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. med. Marcel Naik

Details

Dr. med. Alexander Heinrich Nave, MSc

Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology


alexander.nave@charite.de

    Fields of Research

  • Stroke
  • Biomarkers
  • Metabolism
Details

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. Jawed Nawabi

Details

Dr. med. Mir Timo Zadegh Nazari-Shafti

German Heart Center Berlin, Department of Cardiothoracic and Vascular Surgery


nazari@dhzb.de

    Fields of Research

  • Temlomere Biology
  • Mesenchymal Stem Cells
  • Cardiac Regeneration
Details

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. Marc Joachim Nikolaus

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Dr. med. Christian Oeing

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Dr. med. Maria Olbert, BSc

Charité – Universitätsmedizin Berlin, Department of Anesthesiology and Operative Intensive Care Medicine


maria.olbert@charite.de

    Fields of Research

  • Postoperative Delirium
  • Cholinergic Pathways
  • Geriatric Anesthesiology
Details

Project Title

Association Between Cholinergic System Genetic Variants and Postoperative Delirium and Cognitive Dysfunction

Project Description

Postoperative delirium (POD) is a common neurocognitive complication that can lead to a permanent cognitive dysfunction (POCD). Although the exact pathophysiology is not entirely clear, inflammatory processes within the brain are thought to be involved. There is evidence that a central inflammation can be inhibited by cholinergic neurons, so that any impairment in the cholinergic neurotransmission is thought to be predisposing risk factor for POD/POCD. Due to an accumulation of such predisposing and precipitating risk factors, elderly patients are at a higher risk to develop POD/POCD. In this project, we aim to investigate an association between cholinergic system genetic variants and POD/POCD by examining patients from the BioCog Study (NCT02265263/ www.biocog.eu), which included patients ≥ 65 years undergoing elective surgery. Prior to the operation, patients provided blood samples and completed baseline neurocognitive test batteries. Each patient was visited daily
for the first 7 postoperative days (to detect POD via multiple validated assessment instruments), with regular follow-ups for two years (to detect POCD via neurocognitive testing). Genotyping will be performed with a commercial screening array, allowing for the identification of single nucleotide polymorphisms, insertions, deletions and copy number variations. Genes of interest include genes for cholinesterase, -transferase, -trans- porter and -receptors. Moreover, we will link results of genotyping to the expression profile of the correspond- ing genes, as well as to peripheral cholinesterase activities. The long-term objective is to verify whether genetic variants are potential predictors for POD/POCD. By identifying relevant cholinergic genes via genotyping, which can be sequenced de novo in future projects, we aim to generate new hypotheses for development of POD/POCD.

Dr. med. Florence Pache

Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology


florence.pache@charite.de

    Fields of Research

  • Neuroimmunology
  • Neuro‐Ophthalmology
  • Innate Immunity
Details

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. Yannick Palmowski

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PD Dr. med. Constanze Pfitzer

German Heart Center Berlin, Department of Congenital Heart Disease, Pediatric Cardiology


pfitzer@dhzb.de

    Fields of Research

  • Neurological Outcome of Children and Grown‐Ups with Congenital Heart Disease
  • Hypothermia
Details

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. Dominique Piber

Details

Dr. med. Dominika Pohlmann

Charité – Universitätsmedizin Berlin, Department of Ophthalmology


dominika.pohlmann@charite.de

    Fields of Research

  • Uveitis
  • Immunology
  • Imaging
Details

Project Title

Immunological and Morphological Signatures in Non-Infectious Chorioretinitis to Improve Therapy

Project Description

Non-infectious chorioretinitis, a form of posterior uveitis encompasses a group of potentially blinding disorders, predominantly occurring in the working age group. Birdshot-Retinochoroiditis (BSRC) and Punctate Inner Choroidopathy (PIC) are an organ-specific inflammation with distinct morphological and genetic characteristics. Disease hallmarks manifest as distinct multiple hypopigmented chorioretinal lesions in BSCR, small punctate lesions and choroidal neovascularization in PIC patients. Both diseases show a clinically progressive course with atrophy of the outer neurosensory retina and formation of fibrotic scars in the final stage. The etiology and pathogenesis are largely unknown but considered as driven by an autoimmune response. It is assumed that BSRC is a chronic T-helper 17-cell-mediated inflammation, but t only a few studies with single parameters and a small number of patients were reported. Therefore, the aim of my research project is to identify immunological and
morphological biomarkers in BSCR and PIC patients for better monitoring of inflammatory activity and prediction of disease progression. The T-cell subpopulation will be characterized and phenotyped by mass cytometry. The assessment of morphological signatures will be detected by using multimodal imaging techniques, such as optical coherence tomography, fluorescence- and indo- cyanine green angiography, fundus autofluorescence, and a new non-invasive modality the optical coherence tomography angiography (Pohlmann D et al., Ocul Immunol Inflamm. 2017; Pohlmann D et al. Br J Ophthalmology. 2017). All collected data will be brought into an overall context, in order to get a better understanding of these two diseases and potentially translate to more targeted therapy.

Akira-Sebastian Poncette

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Dr. med. Uwe Primessnig

Details

PD Dr. med. Magdalena Sarah Prüß

Charité – Universitätsmedizin Berlin, Medical Department, Division of Gastroenterology, Infectiology and Rheumatology


magdalena.pruess@charite.de

    Fields of Research

  • Gastroenterology
  • Pain
  • Immune System
Details

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


judith.rademacher@charite.de

    Fields of Research

  • Acute Anterior Uveitis
  • Axial Spondyloarthritis
  • Biomarkers
Details

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. Bianca Raffaelli

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Dr. med. Momsen Reincke

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Dr. med. Dr. med. dent. Carsten Rendenbach

Charité – Universitätsmedizin Berlin, Department of Oral and Maxillofacial Surgery


carsten.rendenbach@charite.de

    Fields of Research

  • Biomechanics
  • Biomaterials
  • Mandible Reconstruction
Details

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


damian.rieke@charite.de

    Fields of Research

  • Targeted Therapy
  • Precision Oncology
  • Tumor Inflammation
Details

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


paul.ritschl@charite.de

    Fields of Research

  • Transplant Immunology
  • Ischemia Reperfusion Injury
  • Organ Allocation
Details

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

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Dr. med. Julian Rogasch

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Dr. med. Tizian Rosenstock

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Dr. med. Rosa Rößling

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Dr. med. Anne Rübsam

Charité – Universitätsmedizin Berlin, Department of Opthalmology


anne.ruebsam@charite.de

    Fields of Research

  • Neurodegeneration
  • Diabetic Retinopathy
  • Oxidative Stress
Details

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. Lynn Jeanette Savic

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Dr. med. Marie Schafstedde

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Dr. med. Laura Katharina Schenk

Charité – Universitätsmedizin Berlin , Medical Department, Division of Nephrology and Internal Intensive Care Medicine


laura‐katharina.schenk@charite. de

    Fields of Research

  • Hypertensive End‐Organ Damage
  • CD4+ Lymphocytes
  • Hippo Signaling
Details

Project Title

Significance of the Transcription Factor TAZ in Lymphocytes for Treg/TH17 Balance and Ang II-Induced End-Organ Damage

Project Description

Immune mechanisms play an important role in the pathogenesis of arterial hypertension; they contribute to both, the development of hypertension and hypertensive end-organ damage. CD4+ lymphocytes are key cell types involved in this pathogenesis, particularly the balance between regulatory T cells (Treg) and IL-17-producing cells (TH17), that both originate from naive CD4+ cells under specific skewing conditions. TH17 cells are associated with hypertension and hypertensive end-organ damage while a protective role is attributed to Treg. Intracellular pathways that balance the differentiation of Treg and TH17 include TGFβ, IL6, RORγT, Hippo/TAZ, HIF1α. All these pathways are also directly influenced by Ang II/AT1R signaling. In this project, we focus on the
Hippo pathway transcription factor TAZ in T cells during Ang II-induced hypertensive end-organ damage. We hypothesized that CD4-specific TAZ deletion is sufficient to prevent Ang II-induced vascular, renal and cardiac dam- age. Further, we characterize the impact of external factors and ultimately the local organ micromilieu (e.g. oxygen supply, osmolarity, extracellular matrix) and molecular signaling regulating Hippo pathway activation in CD4+ T cells under Treg/ TH17 skewing conditions.

Dr. med. Christian Schinke

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Dr. med. Ludwig Schlemm

Charité – Universitätsmedizin Berlin , Department of Neurology with Experimental Neurology


ludwig.schlemm@charite.de

    Fields of Research

  • Health Services Research
  • Decision‐Support Algorithms
  • Acute Ischemic Stroke Care
Details

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.

Dr. med. Frieder Schlunk

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Dr. med. Laura Katharina Schmalbrock

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PD Dr. med. Felix Alexander Schmidt

Charité – Universitätsmedizin Berlin , Department of Neurology with Experimental Neurology


felix.schmidt@charite.de

    Fields of Research

  • Multiple Sclerosis and Neuromyelitis Optica
  • Afferent Visual and Olfactory System
  • Imaging
Details

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

Details

Dr. med. Joanna Barbara Schneider

Charité – Universitätsmedizin Berlin, Division of Neuropediatrics


joanna.schneider@charite.de

    Fields of Research

  • Muscle Stem Cells (Satellite Cells)
  • Epigenetic Changes
  • Critical illness Myopathy
Details

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.

Dr. med. Stefanie Schreiter

Charité – Universitätsmedizin Berlin, Department of Psychiatry and Psychotherapy


stefanie.schreiter@charite.de

    Fields of Research

  • Schizophrenia
  • Pharmacogenetics and ‐epigenetics
  • Functional Neuroimaging
Details

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.

Dr. med. Eva Vanessa Schrezenmeier

Charité – Universitätsmedizin Berlin, Medical Department, Division of Nephrology and Internal Intensive Care Medicine


eva‐vanessa.schrezenmeier@charite.de

    Fields of Research

  • Acute Kidney Injury
Details

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.

Dr. med. Jens Florian Schrezenmeier

Details

Dr. med. Wibke Schulte

Charité – Universitätsmedizin Berlin, Department of Surgery


wibke.schulte@charite.de

    Fields of Research

  • Macrophage Migration Inhibitory Factor
  • Sepsis
  • Emergency General Surgery
Details

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. Leonille Schweizer

Charité – Universitätsmedizin Berlin, Department of Neuropathology


leonille.schweizer@charite.de

    Fields of Research

  • Cancer Genetics
  • Epigenetics
Details

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. Elise Siegert

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Dr. med. Cornelia Skowronek

Charité - Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology


cornelia.skowronek@charite.de

    Fields of Research

  • Parkinson Syndromes
  • Immunoneuropathology
  • Autonomic Nervous System
Details

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.

Dr. med. Lara Mirja Steinbrenner

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Dr. med. Helena Stengl

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Rahel Maria Strobel

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Dr. med. Heiner Stuke

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Dr. med. Thi Minh Tam Ta

Charité – Universitätsmedizin Berlin, Department of Psychiatry


thi‐minh‐tam.ta@charite.de

    Fields of Research

  • Neurobiology of Depression
  • Peripheral Cytochrome P 450 Activity
  • Depression Pathogenesis
Details

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

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Dr. med. Alexander Thieme

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Dr. med. Loredana Vecchione

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Dr. med. Jan Voss

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Dr. med. Carl Weidinger

Charité – Universitätsmedizin Berlin, Medical Department, Division of Gastroenterology, Infectiology and Rheumatology


carl.weidinger@charite.de

    Fields of Research

  • Immunology Metabolism
  • Oncology
Details

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


veith‐andreas.weilnhammer@charite.de

    Fields of Research

  • Bayesian Modelling
  • Computational Psychiatry
  • fMRI
Details

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. univ. MSc. Nikolaus Wenger, PhD

Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology


nikolaus.wenger@charite.de

    Fields of Research

  • Motor Recovery
  • Neuroprosthetics
  • Stroke Research
Details

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

Details

Dr. med. Nicola Wilck

Charité – Universitätsmedizin Berlin, Medical Department, Division of Nephrology and Internal Intensive Care Medicine


nicola.wilck@charite.de

    Fields of Research

  • Inflammation in Cardiovascular Disease
  • Intestinal Microbiome
  • Host‐Microbiome Interaction
Details

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.

Dr. med. Friedrich Wittenbecher

Charité – Universitätsmedizin Berlin, Medical Department, Division of Hematology, Oncology and Tumor Immunology


friedrich.wittenbecher@charite.de

    Fields of Research

  • Immune Reconstitution in Allogeneic Hematopoietic Stem Cell Transplantation
  • Secondary Immune Defects
Details

Project Title

Mobilization of Donor Immunological Memory and its Fate After Allogeneic Hematopoietic Stem Cell Transplantation

Project Description

Loss of the adaptive immunological memory and hampered immune reconstitution after allogeneic hematopoietic stem cell transplantation (alloHSCT) substantially increase the risk for severe infections post alloHSCT, which account for significant morbidity and mortality in transplanted patients. Transfer of donor memory cells along with the stem cell graft importantly contributes to the post-transplant immune protection of the recipient. The graft quality with respect to memory cells and the impact of G-CSF on the immune cell distribution in the graft remain insufficiently understood. Especially the role of G-CSF in mobilizing specific tissue memory cells might be relevant, as these cells may possess distinct antigen specificities. In order to gain further insight into the effect of G-CSF on memory cells, we will characterize memory T and B cell subset composition, antigen specificities and functionalities in stem cell donors before and after G-CSF treatment. Regarding the fate of the transplanted memory cells, we will analyze memory cell subsets in the corresponding recipients and determine their contribution to immune reconstitution and protection. In this context, we will further assess the impact of the integrity of the bone marrow niche on long-term memory survival. In connection with clinical data, these studies could help to develop treatment strategies such as niche protection or antigen-specific adoptive cell therapy to improve post-transplant immune competence.

Dr. med. Friedrich Wittenbecher

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Dr. med. Jonas Wizenty

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Dr. med. Thomas Heinrich Wurster

Charité – Universitätsmedizin Berlin, Department of Cardiology


thomas‐heinrich.wurster@charite.de

    Fields of Research

  • Cardiovascular Imaging
  • Positron Emission Tomography/ Magnetic Resonance (Imaging)
Details

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

Details

Dr. med. Kun Zhang

Charité – Universitätsmedizin Berlin, Department of Cardiology


kun.zhang@charite.de

    Fields of Research

  • Calcium Signaling in Heart Failure
  • Excitation‐Secretion Coupling in Cardiomyocytes
Details

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. Marco Zierhut

Details

Dr. med. Sebastian Zschaeck

Charité – Universitätsmedizin Berlin, Department of Radiation Oncology and Radiotherapy


sebastian.zschaeck@charite.de

    Fields of Research

  • Functional Imaging
  • Normal Tissue Effects of Radiotherapy
  • Tumor Hypoxia
Details

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.