Program fellows

PD Dr. med. Güliz Acker
Charité – Universitätsmedizin Berlin, Department of Neurosurgery with Pediatric Neurosurgery
Email: gueliz.acker@charite.de
Fields of Research
- Moyamoya Disease
- Glioblastoma Multiforme
- Vascular Targeting
- Brain Metastases
Project Title
Inhibition of the CXCL2/CXCR2 Signaling Pathway in Glioblastoma Multiforme as a Therapeutic Option
Project Description
Glioblastoma multiforme (GBM) is the most common and most malignant astroglial brain tumor with an overall median survival of around 15 months. Despite intensive research in recent decades on new therapeutic strategies no considerable advance in glioma treatment was achieved. Thus, novel and innovative therapeutic approaches are required to prolong survival and improve the quality of life for patients with malignant astroglial tumors. High angiogenesis of GBM is one of the causes of high malignancy, thus angiogenesis represents one of the promising therapeutic targets. However, the therapeutic effect of antiangiogenic treatments has been so far limited by diverse resistance mechanisms. Beside the strong vascularization of gliomas, a high accumulation of microglia/macrophages was shown. In addition, Roggendorf et al. proposed a direct correlation between the grade of gliomas and the number of tumor-associated microglia and macrophages. Therefore, these immune cells could represent an effective therapeutic target. We have already published that resident microglia are the main source of brain tumor mononuclear cells, thus these cells represent a promising novel therapeutic target for patients suffering from this tumor. We observed in our glioma mouse model that depletion of microglia/ macrophages resulted in diminished angiogenesis and reduced tumor volumes. We have also discovered a potential new feature of microglia/macrophages in a glioblastoma mouse model by secreting different chemokines. Due to high overexpression as well as indications in the literature the potential contribution of CXCL2 to glioma angiogenesis awakened our interest at most. Thus, the aim of our study it to establish a new therapy with blocking CXCL2 signal way induced angiogenesis in gliomas and to analyze the role of this pathway in recurrent GBM.
Dr. med. Seven Johannes Sam Aghdassi
Charité – Universitätsmedizin Berlin, Institute for Hygiene and Environmental Medicine
Email: seven-johannes-sam.aghdassi@charite.de
Fields of Research
- Automated Surveillance
- Healthcare-Associated Infections
- Applied Infection Control
Project Title
Semiautomated surveillance of surgical site infections
Project Description
Surgical site infections (SSIs) are among the most frequently occurring healthcare-associated infections (HAIs) in German hospitals and complicate the postoperative recovery of operated patients. The German Protection against Infection Act (“Infektionsschutzgesetz”) requires all hospitals in Germany to routinely conduct surveillance of HAIs. Conventional surveillance of HAIs, or more specifically SSIs, requires the manual review of patient charts and represents a time-consuming and resource-intensive process. As a result, surveillance of SSIs is often limited to only a few departments and procedures. Automation of certain steps of the surveillance process may represent a viable solution to overcome this limitation.
Our project aims to establish a semiautomated method for the surveillance of surgical site infections, in which an algorithm evaluates patients who have undergone surgical procedures, and pre-selects patients with suspected SSIs. Only for these pre-selected patients, a manual chart review will be required. Consequently, the workload for conducting surveillance of SSIs will be reduced considerably. In order to achieve an algorithm capable of performing this task, data from different sources (e.g. patient-related data, procedure-related data, and microbiological findings) will be migrated into a data warehouse, in which a data-driven classification system will be operated. The underlying algorithm for the classification system will be created using a machine learning approach utilizing retrospective data. The semiautomated surveillance systems is intended for application first at surgical departments at Charité-Universitätsmedizin Berlin. Once a functioning algorithm and method will have been created, it is aspired to implement the semiautomated surveillance system at other suitable hospitals in Germany. The existing surveillance network “KISS” with over 1,000 participating hospitals in Germany, may serve as a basis for a national rollout of the system.
Dr. med. Martin Atta Mensah
Charité – Universitätsmedizin Berlin, Institute of Medical Genetics and Human Genetics
Email: martin‐atta.mensah@charite.de
Fields of Research
- Exomics
- Syndromology
- Computer‐Aided Photogrammetry
Project Title
Prioritization of Exome Data by Image Analysis
Project Description
The rapid development of new sequencing methods (Next Generation Sequencing) enables the fast and cost-effective analysis of all human genes. This development presents human genetics and in particular clinical genetics with the challenges of interpreting the large amounts of generated data. Among the thousands of neutral sequence variants, the one pathogenic mutation has to be found. Various bioinformatic approaches have been developed, which are based on the clinical-phenotypic description of the investigated patient (physical appearance, symptoms, laboratory findings ...) and on the properties of the detected variants (altered gene, allele frequency, degree of evolutionary conservation, type of variant ...). These methods offer good results, but there is still room for improvement. In clinical genetics, the face of a patient traditionally plays a key role in determining the diagnosis as approx. 40% of hereditary syndromological diseases show characteristic abnormalities of the facial morphology. Knowledge of these abnormalities is therefore of particular value for the clinical geneticist. The large number of hereditary syndromes (there are several thou- sand) and the rarity of the individual disease entities re- quire expertise based on decades of clinical experience. Modern machine-learning based image recognition pro- grams are able to learn these specific features of the facial gestalt from ordinary frontal photos of patients with genetic-syndromological diseases. Our research aims to evaluate these methods and to develop a machine-learning based pipeline, which– in addition to prior approaches- includes automated facial photogrammetry in sequence data analysis to enable an even more efficient diagnostic procedure.
Dr. med. Timo Alexander Auer
Charité – Universitätsmedizin Berlin, Department of Anesthesiology and Operative Intensive Care Medicine
Email: timo-alexander.auer@charite.de
Fields of Research
- Multimodal liver imaging
- Interventional therapy of liver tumors
- MR imaging of glioma
Project Title
MRI Morphologic Noninvasive Subclassification of Hepatocellular Carcinomas – The »HepCasT«-Study
Project Description
Hepatocellular carcinomas (HCCs) are a heterogeneous group of tumor subtypes with a different response behavior and prognosis. As a reaction, the World Health Organization (WHO) in its 5th version (updated in 2019) classifies no more two but eight subtypes, each with a different tumor biology and outcome. The new classification may serve as a key factor optimizing a more personalized therapeutic approach and therefore, especially diagnostic disciplines have to implement these new subtypes as soon as possible into their daily clinical routine algorithms. Imaging does play a key role in this situation. Newer and advanced MRI techniques allow a precise
tissue characterization. Furthermore, with the help of latest generation hepatobiliary contrast agents it is possible to quantify and measure the organ function and specific uptake behavior of focal liver lesions. Another approach that hold promise for advancing the characterization of HCCs heterogeneity is the use and development of artificial intelligence (AI)-based image postprocessing
algorithms including radiomics analysis. To date there aren’t any established imaging features correlating with any of the new WHO HCC-subtypes. The goal of our project is to identify imaging biomarkers correlating with the new HCC-subtypes, helping to classify them noninvasively. As a next step with the help of our collaborators we will facilitate a radiological-pathological reference database. In a third step and with the help of the data we curated we will try to identify morphologic imaging characteristics by the use of AI-based post-processing algorithms to classify the subtypes noninvasively and to predict / estimate patients individual therapy response and prognosis. The last challenge will be to implement these algorithms into daily clinical routine, we therefore have to identify interface dilemmas and present smart solutions to solve them. We are convinced that by implementing the updated WHO-criteria into clinical workflows current believes and guidelines in the diagnosis and therapy of HCC will change. The results of our project may provide the knowledge to represent as a cornerstone in imaging and therapy assessment of HCC to improve a personalized therapy approach.
Dr. med. Magdalena Balcerek
Charité – Universitätsmedizin Berlin, Department of Pediatrics, Division of Oncology and Hematology
Email: magdalena.balcerek@charite.de
Fields of Research
- Paediatric Oncology and Haematology
- Fertility Impairment
- Quality of Life
Project Title
Prevalences, Risk Factors and Dynamics of Fertility Impairment in Patients with Chronic Anaemia
Project Description
Diseases causing chronic anaemia require constant monitoring and treatment to avoid potentially life-threatening complications. Improvements in medical treatment in recent years has notably raised patient prognosis. Therefore, long-term consequences of the underlying disease and/or the necessary treatments as well as quality of life of those affected are of increasing relevance. A key aspect of high quality of life is successful family planning. However, patients with different anaemia may suffer from fertility impairment. FeCt-HAEMATOLOGY aims to identify prevalences, disease and therapy-related risk factors and dynamics of fertility impairment in adolescents and adults with different anaemia as well as the psycho-social relevance of successful family planning for those affected. The study will be conducted as a multicentre retro- and prospective study in cooperation with disease-specific registries and working groups in centres for paediatric and internal medicine in Germany, Austria and Switzerland. The psycho-social relevance of successful family planning, patient education and utilization of fertility preservation will be assessed with the help of a patient questionnaire. Medical data, such as patient core data (sex, date of birth, diagnosis and date of diagnosis) and data on pubertal development, pregnancies and births as well as clinical and laboratory findings, results of fertility testing and therapy data will be collected from patient files/ data bases for data analyses. Findings will be distributed to the disease- and treat- ment-specific registries and working groups. Project output will help to (1) improve therapeutic strategies to reduce adverse late effects, (2) assist therapists and patients in optimizing family planning and (3) determine timing and choice of fertility-preserving measures and/or reproductive therapies.
Dr. med. Alexej Ballhausen
Email: alexej.ballhausen@charite.de
Fields of Research
- Multiple Myeloma
- Clonal evolution
- Single cell technologies
Project Title
Cellular relatedness and genetic diversity of multiple myeloma at the single cell level
Project Description
Multiple myeloma is a hematologic malignancy characterized by accumulation of monoclonal plasma cells in the bone marrow. Extensive bone marrow infiltration and production of monoclonal immunoglobulin or light chains can cause life-threatening complications including infections, renal failure, amyloidosis, bone fractures, and bone marrow failure, among others. Although a variety of novel treatment options can induce remissions, multiple myeloma frequently relapses and remains incurable. Due to the nature of the disease (malignancy of the B lineage), multiple myeloma cells within individual patients carry identical immunoglobulin sequences, which can be used as highly sensitive biomarkers and characteristic molecular barcodes to track the disease. In addition, a variety of somatic mutations have been identified in multiple myeloma. However, the impact of distinct mutational patterns or distinct B cell populations on disease progression remains unclear. Moreover, the cell of origin in multiple myeloma has been under debate. Although accumulating malignant cells are predominantly plasma cells and substantial numbers of somatic hypermutations within immunoglobulin genes suggest that the disease arises at the post-germinal center stage of B cell development, their immune phenotypes can be diverse and include even normal-phenotype B cells.
We aim to 1) define the phenotypic range of multiple myeloma at the single cell level, 2) identify developmental trajectories of monoclonal B lineage cells and 3) identify populations at developmentally early stages for selective isolation and translational therapeutic targeting. We will determine high-dimensional immune phenotypes, immunoglobulin sequences, and somatic mutations in parallel at the single cell level in thousands of bone marrow B lineage cells from 15 treatment-naïve multiple myeloma patients. This project addresses the unmet medical need to identify cell populations that are critically involved in multiple myeloma development and represent potential targets for translational therapeutics.
Dr. med. Frederik Bartels
Charité – Universitätsmedizin Berlin, Department of Neurology and Experimental Neurology
Email: frederik.bartels@charite.de
Fields of Research
- Autoimmune Encephalitis
- Neuroimmunology
- Neuroimaging
Project Title
Longitudinal Structural Brain MRI Analysis and Cognitive Outcome in Anti-NMDA-Receptor Encephalitis
Project Description
Anti-NMDA receptor encephalitis (NMDARE) is the most common form of autoimmune encephalitis, a group of recently identified autoantibody-associated inflammatory brain disorders. It mainly affects young women and children but can occur at any age. The clinical course is usually monophasic with severe neurological and neuropsychiatric symptoms. Most patients have a good outcome based on physical disability after 24 months. However, recent studies and observations from clinical practice show considerable cognitive deficits after the acute phase. The long-term outcome and course of these cognitive deficits as well as the underlying mechanisms are still unknown and have not been systematically investigated. Interestingly, structural brain damage visualized on routine cerebral magnetic resonance imaging (MRI) has only been identified in around 50% of patients, despite a severe clinical course in most cases. Previous studies indicate that the presence of MRI changes correlates with a worse outcome. However, a systematic classification of these MRI changes and in particular their clinical relevance remains unclear. The aim of this project is, therefore, to systematically investigate i) the longitudinal structural brain damage using advanced quantitative MRI techniques and ii) assess its role as a possible correlate and predictor for persistent clinical and cognitive long-term deficits in NMDARE patients. The detailed MRI analyzes combined with specific assessments of neuropsychological and clinical outcome will help to better understand the disease mechanisms and longterm effects of this autoimmune brain disease. Overall, the project will thus contribute to increase diagnostic accuracy and identify more personalized therapeutic strategies in order to improve long-term outcome and help regain full cognitive performance and quality of life in these mostly young patients.
Dr. med. Aitomi Bittner
Charité – Universitätsmedizin Berlin, Medical Department, Division of Hematology, Oncology and Tumor Immunology
Email: aitomi.bittner@charite.de
Fields of Research
- Lymphomagenesis
- Personalized Medicine
- Patient‐Derived Xenografts
Project Title
Establishment of a Patient-Specific Syngeneic Immune and Lymphoma PDX-Model for Functional Lymphoma Pathogenesis, Therapy-Prediction and Biomarker-Development
Project Description
Experimental studies in animal models, particularly in transgenic mice models, led to a fundamental under- standing of the functional role of activated oncogenes and inactivated tumor suppressor genes as well as of stress-response-programs as apoptosis or cellular senescence in human lymphoma. However, due to species differences, these models can only recapitulate parts of the temporospatial genetic complexity of human lymphoma pathogenesis. In order to recapitulate human biological systems more closely, sophisticated small-animal models are acutely required. Systemic-orthotope propagation of primary patient-derived tumor-material in immunodeficient mice (so-called »Patient-derived Xenografts [PDX]«) is one solution. These PDX-lymphoma-models are particularly attractive, because a previous transplantation of syngeneic hematopoietic stem and progenitor cells (HPSC) achieves a human-reconstitution of hematopoiesis and immune system, leading to a very extensive humanization of tumor-microenvironment in bone marrow, lymph node, spleen, thymus and peripheral blood. By now, specific profoundly immunodeficient mice are developed. This allows an efficient engraftment of HSPCs with subsequent development of all significant immune cell populations. The general aim of this project is to reconstitute patient-specific syngeneic immune and lymphoma cells in humanized PDX-mice as a clinical relevant test-platform for the investigation of lymphoma-pathogenesis, personalized therapy-response and biomarker-development. A long-term aim of this clinical-translational project is to use this lymphoma-mouse-model for prediction of individual therapy response to one or a combination of new targeted-therapies, biologicals, and antibodies.
Marie Bossen
Charité - Universitätsmedizin Berlin, Charité Comprehensive Cancer Center (CCM)
Email: marie.bossen@charite.de
Fields of Research
- precision oncology
- preclinical cancer models
- tumor microenvironment
Project Title
Establishment of representative 3D model systems of metastatic colon cancer for rapid pharmacotyping
Project Description
Despite early diagnosis through the widespread use of screening strategies and improved treatment regimens, colorectal cancer (CRC) still represents the second most common cause of cancer-related mortality. Especially the metastatic stage (mCRC), in which nearly a quarter of patients are diagnosed, is characterized by a dismal prognosis. Thus, mCRC remains a major clinical challenge that makes the development of clinically relevant in vitro models for preclinical drug testing and guidance of personalized treatment approaches crucial to improve patient’s survival rates.
The aim of our research project is to develop representative model systems that reliably reflect the biology and complexity of mCRC in order to increase the successful translation of in vitro results into clinical practice. Therefore, three different patientderived 3D model systems of mCRC are established and compared to the original tumors in terms of their cellular composition and molecular characteristics by performing cell stainings and multi-omics approaches (mutational profiling, proteomics). To allow clinical implementation, the preclinical drug testing procedure is optimized to reduce the time span between sample collection and the report of drug sensitivity.
Dr. med. Tim Bastian Brämswig
Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology
Email: tim‐bastian.braemswig@charite.de
Fields of Research
- Silent Brain Infarcts
- Cerebral Imaging in Stroke
Project Title
Silent Brain Infarcts – Incidental Finding or Risk Factor?
Project Description
Ischemic brain lesions in cerebral imaging without a matching clinical syndrome are described as silent brain infarcts. Silent brain infarcts appear frequently in the general population and are associated with future strokes and dementia. Others and we have reported that subsequent new diffusion-weighted imaging (DWI) lesions on magnetic resonance imaging (MRI) are also common in patients with a clinically manifest acute ischemic stroke. In our study, new DWI lesions were detected in 38% of the study population within one week after the initial ischemic event. Clinical stroke recurrence occurred in only 2%. Thus, most of the new DWI lesions appeared clinically silent (Braemswig et al, Stroke 2013). Additionally, patients with elevated glycated hemoglobin (HbA1c) were found to have an increased risk for new, de novo DWI lesions in the acute phase after an ischemic stroke (Braemswig et al., Front. Neurol. 2017). Silent brain infarcts appear often during certain operative and interventional procedures. In cooperation with the Department of Cardiology, we want to describe frequency and distribution of new DWI lesions on MRI following Mitra- Clip procedure. Besides, we perform continuous transcranial Doppler ultrasonography (TCD) during MitraClip procedure to detect microembolic signals (MES) and to allocate MES to specific phases of the procedure.
Dr. med. Katarina Braune
Charité – Universitätsmedizin Berlin, Department of Pediatrics, Division of Endocrinology and Diabetology
Email: katarina.braune@charite.de
Fields of Research
- Telemedicine
- Big Data
- Value‐Based Health Care
Project Title
Digital Diabetes Clinic (DDC) – A Pioneer Project in Value-Based Health Care
Project Description
Diabetes represents a growing challenge for health systems everywhere. Its prevalence has been continuously growing over the last decades, with the financial and human burden on health care systems increasing as a result. For children and adolescents living with diabetes, innovative treatment options involving insulin pumps and continuous glucose monitoring systems are available today. However, to benefit the most from the use of these tools, a high level of patient empowerment and self-care is essential. Furthermore, a higher level of digitalization in the respective hospital is required. Without appropriate tools for data collection and analysis, a vast amount of useful patient data does not get assessed and is therefore lost potential for better patient outcomes. We have experienced that conventional visits in our diabetes outpatient clinic and inpatient admissions to our hospital ward put our patients in an artificial time window. Rarely do they represent daily challenges and actual needs of our patients. A paradigm shift is needed in how health services are delivered, managed, and funded. Integrated Care Pathways (ICPs) are one of the current most promising strategies with a novel approach to mutual-decision making and organization of care. ICPs are personalized, structured multidisciplinary care plans aiming to enhance health-related quality of life by improving patient outcomes, promoting patient safety, increasing patient satisfaction, and optimizing the use of resources. From a patient’s perspective, integrated care aims to meet their health and social needs, taking these as a starting point for redesigning their care. This project aims to investigate quality of care (patient outcomes, patient and health care professional satisfaction) using an integrated platform for patient data assessment and performing mobile clinic visits through telemedicine as a first step of a new ICP plan. Furthermore, we intend to analyse success factors and barriers for our Paediatric Diabetes Unit on its way from conventional care to a digital clinic. With this novel approach in Paediatric diabetes care, we hope to serve as a lighthouse project for management plans for more chronic diseases in Paediatric and Adult Care of the Charité – Universitätsmedizin Berlin, as well as for Paediatric and Adult Diabetes Centres worldwide.
Georg Braune
Charité - Universitätsmedizin Berlin, Institut für Biochemie und Molekularbiologie (CCM)
Email: georg.braune@charite.de
Fields of Research
- Developmental Biology
- Neurology
- Organoid Research
Project Title
Notch3-dependent control of Neural Stem Cells behavior in a human iPSCs-derived cerebral organoids model of CADASIL
Project Description
The nervous system is in many ways the most complex tissue in an organism. It contains many different cell types that with their interactions build a network out of which emerge our thoughts, feelings and our personality. The process of the development and maintenance of this system is called neurogenesis. It is orchestrated by the interplay of many different signaling pathways both during embryonal development and adulthood. One of them is the Notch3 signaling pathway that was shown in zebrafish and mice to have a high importance in maintaining neural stem cell quiescence in the adult brain (Alunni et al., 2013, Kawai at al., 2017). The involvement of Notch3 in human neurogenesis is yet to be discovered.
In humans, mutations in Notch3 lead to the CADASIL syndrome, a yet incurable disease representing the most common inheritable cause of strokes (Chabriat et. Al, 2009). Besides that, CADASIL patients show progressive cognitive decline ultimately leading to severe dementia. Given the fact that Notch3 is known to regulate vascular smooth muscle cell function and maturation of arteries (Wang et al., 2007) and considering the vascular occlusions observable in the brains of affected patients, CADASIL is currently classified as a disease of the vasculature with neuronal defects considered to be a secondary consequence. However sometimes cognitive decline occurs before vascular occlusions (Amberla et al., 2004) and considering the importance of Notch3 in
regulating neurogenesis in other organisms we hypothesize a primary neuronal phenotype in CADASIL syndrome that is independent of vascular impairments.
Here we use cerebral organoids as a vasculature-free model to investigate the role of Notch3 during human neurogenesis (Lancaster et al., 2013). To do so we generate cerebral organoids from induced pluripotent stem cells (iPSCs) derived from skin fibroblasts from patients with the CADASIL syndrome and from iPSCs with a full Notch3 knockout. In these organoids we will quantify stem cell fate choices by combining markers of different progenitor populations with BrdU-lineage tracing.
PD Dr. med. Keno Bressem
Charité – Universitätsmedizin Berlin, Department of Radiology (including Pediatric Radiology)
Email: keno-kyrill.bressem@charite.de
Fields of Research
- Deep Learning in Computer Vision and Natural Language Processing Focussed on Radiology
Project Title
Improving the Generalizability of Radiological Deep Learning Models Through a Prospective Study Infrastructure
Project Description
Translating deep learning models into clinical practice is a fundamental challenge and is expected to grow in importance. Deep learning models often suffer from low generalizability when applied to new data, which means that the accuracy of the models used is much lower than the accuracy achieved during development under controlled conditions. To prevent this, deep learning models should be clinically tested before they are used. To accelerate this process, I am developing an infrastructure at Charité Universitätsmedizin Berlin to facilitate the prospective evaluation of deep learning models. Together with my team, we aim to integrate deep learning algorithms into the radiological productive system (the Picture Archiving and Communication System – PACS). This will allow us to immediately test and continuously improve developed algorithms until they are highly reliable and can be used in clinical practice.
Dr. med. Leon Alexander Danyel
Charité – Universitätsmedizin Berlin, Department of Neurology and Experimental Neurology
Email: leon.danyel@charite.de
Fields of Research
- Neurovascular disorders
- Diffusion-weighted imaging
- Ocular vascular occlusive disorders
Project Title
Retinal Diffusion-Weighted Imaging in Central Retinal Artery Occlusion
Project Description
Central retinal artery occlusion (CRAO) constitutes a medical emergency as it leads to persistent and debilitating visual impairment of the affected eye. As the chance for visual recovery decreases with the duration of retinal ischemia, therapeutics to achieve retinal reperfusion have to be administered as early as possible. We recently identified retinal diffusion restrictions (RDR) as a frequent finding in CRAO patients on standard brain diffusion-weighted magnetic resonance imaging (DWI MRI). Our research aims to further investigate RDR and their utility for early diagnosis in CRAO with a series of retrospective and prospective clinical trials. Our main focus lies on the application of novel DWI sequence techniques, such as readout-segmented DWI and small field of-view DWI to improve the detection of diffusion restrictions in retinal ischemia. Finally, we hope to further expand the application of retinal diffusion-weighted imaging as a diagnostic modality to other ocular vascular occlusive diseases.
Dr. med. Natasha Darcy
Email: natasha.darcy@charite.de
Fields of Research
- Movement Disorders
- Genetic Parkinson's Disease
- Deep Brain Stimulation
Project Title
Elektrophysiologische Merkmale der genetischen versus sporadischen Parkinson-Erkrankung anhand von Tiefenableitungen
Project Description
Research into the genetic basis of neurodegenerative diseases is expanding as the potential for preventative or curative measures to combat these widespread and debilitating progressive diseases is recognised. In Parkinson’s disease (PD), the past three decades have produced more than twenty genetic variants associated with a higher risk for developing the disease, often at a younger age and sometimes with characteristic disease course.
In deep brain stimulation (DBS), an increasingly common treatment for medically resistant PD, electrodes are implanted into the basal ganglia, most often the subthalamic nucleus (STN). By applying electrical current, DBS is effective at modulating the pathological network activity and improving symptoms. Conversely, it allows unprecedented insights into subcortical brain activity by measuring so-called local field potentials around the electrodes. Pathologically synchronised activity in the beta frequency range (13-30 Hz) measured by these electrodes is known to correlate with symptom load. To this day, it remains unclear how exactly this reflects the pathology of PD, at which stage in disease progression it appears and where it falls on the spectrum of hallmark to epiphenomenon of disease pathology.
Research into genetic PD, including whether beta activity is present in these types has important consequences for both pathophysiological understanding and for treatment options regarding DBS and, more specifically, adaptive DBS. Still in development, current strategy often relies on STN beta-activity as the physiomarker for triggering stimulation. For patients with genetic PD, who are often younger at disease onset and stand to profit from the advantages, namely reduction of side effects and sparing of battery life, it is therefore crucial to discover whether this marker is reliable. With the time allocated to me by the Junior Clinician Scientist program, I aim to gather both retrospective and prospective deep brain recordings from genetic and sporadic PD patients undergoing STN-DBS in order to compare the electrophysiological profiles and most notably the presence or absence of characteristically enhanced beta activity.
This research will facilitate pathophysiological understanding of this physiomarker and be an important guide to patients with genetic Parkinson's disease considering treatment with deep brain stimulation.
Dr. med. Ana Luisa de Almeida Marcellino
Charité – Universitätsmedizin Berlin, Department of Neurology and Experimental Neurology
Email: ana.almeida@charite.de
Fields of Research
- Cerebral palsy
- Functional connectivity
- Deep brain stimulation
Project Title
Functional Networks of Dyskinetic Cerebral Palsy: a Lesion-Based Study
Project Description
Infantile cerebral palsy is a broad term for pre- or perinatally acquired, non-progressive, predominantly motor disorders that can affect muscle tone, strength and/or posture. The dyskinetic subtype represents 10-14% of all cases and is characterised by the presence of complex hyperkinetic movement disorders including dystonia and choreoathetosis. Current treatment is solely symptomatic and largely unsatisfactory. Dyskinetic cerebral palsy (dCP) is associated with lesions in the basal ganglia, thalamus and cerebellum. To what extent lesion characteristics such as specific location or functional connectivity are associated with clinical movement disorder patterns is still not clear. Deep brain stimulation (DBS) is an established treatment for Parkinson’s disease or primary dystonia and is known to modulate abnormal motor network activity. In contrast to primary dystonia, DBS of the globus pallidus internus for patients with dCP has shown heterogeneous results. Understanding which functional networks underlie specific movement disorder patterns in dCP might facilitate patient and target selection for neuromodulatory treatments such as DBS. In this study, we hypothesise that different clinical movement disorder patterns (e.g. predominant dystonia or chorea) in dCP are related to lesions in specific nodes of larger functionally connected networks. To test this hypothesis, 30 patients with dCP will undergo a thorough clinical examination aimed at characterising the clinical movement disorder pattern. In a second step, cranial MRIs of included patients will be analysed and existing lesions delineated in order to investigate their association with the individual movement disorder. Lastly, perturbed functional networks underlying different movement disorder patterns in patients with dCP will be identified using lesion network mapping. On the longterm, these findings could be used to explore targeted treatments for dCP, taking into account individual clinical phenotypes of this heterogeneous disease entity.
Dr. med. Sophy Denker
Charité – Universitätsmedizin Berlin, Department of Hematology, Oncology and Cancer Immunology
Email: sophy.denker@charite.de
Fields of Research
- Hematology & Oncology
- Multi-Omics
- Lymphoma Biology
- Machine Learning
- Novel Study Design
Project Title
Anticipation, Prediction and Optimization of the Therapeutic Outcome of Lymphoma Patients Using Digital Model Analysis
Project Description
In order to improve the long-term survival of high-risk lymphoma patients by personalized medicine, the development of new prediction parameters through a multimodal evaluation approach is necessary. This interdisciplinary project in close cooperation with Prof. Dr. Roland Eils at the BIH Center for Digital Health combines clinical data, basic tumor biology research, and current bioinformatics analysis methods and is thus unique to this point and represents an innovative and conceptual new orientation of tumor precision medicine.
PD Dr. Hedwig Deubzer
Charité – Universitätsmedizin Berlin, Department of Pediatric Oncology and Hematology
Email: hedwig.deubzer@charite.de
Fields of Research
- Pediatric Precision Oncology
- Liquid Biopsies
- Diagnostics development
Project Title
Liquid biopsy-based diagnostics for pediatric solid tumors
Project Description
The Deubzer laboratory research program addresses the three central monitoring areas essential for optimal personalized treatment of children with high-risk neuroblastoma: (1) therapy response assessment, (2) minimal residual disease monitoring and (3) actionable target identification. The primary aim is to accelerate transfer of liquid biopsy-based approaches to the clinic within these monitoring areas to make clinical phenotypes of residual, refractory and/or relapsed disease predictable. Implementing our molecular techniques to characterize cell-free nucleic acids, proteins, metabolites and exosomes in biofluids is expected to improve patient monitoring, secondary treatment selection and, ultimately, overall patient survival. Liquid biopsies are likely to better reflect spatial intratumor heterogeneity, tumor evolution and drug sensitivities, thereby, greatly contributing to personalized medicine. Our analyses are focused on validating recently identified candidate biomarkers in large patient cohorts and on expanding the existing biomarker portfolio. A newer focus is translating predictive biomarkers/signatures identified in multi-omics data from liquid biopsies into diagnostic kits for clinical application. We assess test sensitivity in multicenter round robin tests, and measure complementarity in predictive power within the framework of clinical trials. Maintaining, expanding and updating the biobanking infrastructure, technology platforms and data analysis tools supporting the paradigm shift towards personalized care of patients with high-risk neuroblastoma is an underlying essential part of work in the Deubzer laboratory, which we have plans to extend to pediatric patients with other serious and debilitating solid cancers.
Dr. med. Jan Rafael Dörr
Charité – Universitätsmedizin Berlin, Department of Pediatric Oncology and Hematology
Email: jan-rafael.doerr@charite.de
Fields of Research
- Cancer
- Senescence
- Cancer Immunotherapy
Project Title
Development of Minimal Invasive Diagnostic Tools and Targeted Therapies for Tumor Cell Senescence
Project Description
Despite our rapidly expanding knowledge of cancer genomes and their mutational landscapes, the functional understanding of cellular failsafe programs, which prohibit cancer development and which underly cancer treatment principles, remains incomplete. Alongside apoptosis premature senescence represents a major cellular failsafe mechanism in both mice and men, since it induces a terminal proliferation arrest of viable tumor cells. In this way senescence controls tumor growth as part of cytotoxic therapies. Although therapy-induced senescence (TIS) can prolong tumor-free survival and improve treatment outcome, senescent tumor cells also acquire harmful characteristics: They display an increased stemness potential and persistently remodel their tissue environment predominantly through their enhanced secretory activity. In this way senescence contributes to treatment resistence. However, diagnostic tools, which faithfully detect TIS in the clinic and which could subsequently guide treatment decisions, are largely missing. Moreover, the targeted elimination of senescent tumor cells presents a weakly explored therapeutic opportunity. In the Clinician Scientist Program I therefore aim to elucidate senescence-induced modifications of the tumor stroma and the immune system predominantly in mouse lymphoma as well as neuroblastoma models with the goal to develop minimal invasive senescence screens and to explore novel senescence treatment strategies.
Dr. med. Wiebke Düttmann-Rehnolt
Charité – Universitätsmedizin Berlin, Department of Nephrology and Medical Intensive Care
Email: wiebke.duettmann@charite.de
Fields of Research
- Kidney Transplantation
- Surveillance of Immunosuppressed Patients
- Opportunistic Infections
- Digitalization of Health Care System
Project Title
Intersectoral eHealth concept of care in patients with an OPAT
Project Description
Patients with certain infections require long-term intravenous (IV) antibiotic therapy, and, as IV therapy is usually only possible at hospital, patients need to stay there although they feel well after a short period. Outpatient parenteral antibiotic therapy (OPAT) is an innovative approach, which enables patients with long-term IV antibiotic therapy, to go home and applicate antibiotics on their own or with help of specialized nurses.
However, data silos as well as no or little communication between patients, OPAT-nurses, and doctors lead to complications and misunderstandings. Patients feel alone and some even scared. Doctors are insecure. Thus, only a small group receives access to this modern concept. The current project builds on an existing digital infrastructure with a patient app, electronic health record (EHR) called TBase, and telemedicine team. Aims of this current project are (1) to design a patient journal to support the connection between patients with OPAT and the doctors as well as nurses via an app, (2) to integrate a sufficient “eRezept” compatible to Gematik, (3) to visualize microbiological test results in the mentioned EHR via logical observation identifiers names and codes (LOINC), (4) to design an app in order to seek questionnaires for patient reported outcome measures (PROMS) via health level 7 (HL7) and fast healthcare interoperability resources (FHIR) and visualization in the EHR via LOINC, and finally (5) to initiate the implementation of SNOMED CT.
The patient journey shall, in a first step, be developed in the frame of an explorative and observational study, and, in a second step, be evaluated for usefulness by a multicenter randomized controlled trial.
Dr. med. Tomasz Dziodzio
Charité – Universitätsmedizin Berlin, Department of Surgery
Email: tomasz.dziodzio@charite.de
Fields of Research
- Obesity
- Kidney transplantation
Project Title
Pathomechanisms of Obesity in the Field of Kidney Transplantation
Project Description
Morbid obesity is a globally increasing disease and affects 23% of the population in Germany. It is associated with numerous co-morbidities and a high mortality. Obese kidney transplant recipients show higher rates of delayed organ function and rejections. Therefore, obese kidney transplant candidates are often denied access to organ transplantation. In Germany 50% of transplantation centers use body mass index-linked thresholds as a selection criterion to grant access to the transplant waitlist. Bariatric surgeries are discussed as a solution to this ethical dilemma. Their safety and effectiveness have been confirmed in case studies and retrospective analyses, but positive effects on organ and patient survival have not been proven prospectively. Furthermore, it has been shown that the expression of inflammatory markers, such as IL-6 and TNF-α, as well as CD4+ and CD8+ T lymphocytes can be affected by bariatric surgeries. However, it is still unclear what additional value this represents for transplant candidates. This project aims to investigate the impact of obesity and weight loss therapies for patients before and after kidney transplantation. We plan to investigate the pathomechanisms of obesity on graft function and the immunological response in a rat model with obese Zucker Diabetic Fatty rats. In addition, a clinical program for obese kidney transplant candidates will be initiated to determine the metabolic and immunological effects of conservative versus surgical weight reduction programs in these patients.
Dr. med. Felix Ehret
Email: felix.ehret@charite.de
Fields of Research
- Translational Neuro-Oncology
- Cancer Epigenetics
- Image-guided Robotic Radiosurgery
Project Title
The Role of Radiotherapy in the Treatment of Atypical Meningiomas – A Methylome- and Genome-based Analysis
Project Description
Meningiomas are the most common intracranial tumors of the central nervous system (CNS). With the revised WHO classification of tumors of the CNS in 2016, molecular markers were introduced to further specify and distinguish certain tumor subtypes. The diagnosis of meningiomas, however, is still solely based on histopathological features. Recently, DNA-methylation-based classifiers have shown to accurately predict and stratify CNS tumors to improve the standardization of tumor diagnostics. The traditional approach of meningioma diagnosis using only light microscopy and immunohistochemistry to distinguish the current fifteen subclasses is prone to interobserver biases and limited regarding risk stratification and personalized treatment decision making. With approximately 80% of meningiomas showing benign behavior (WHO grade I) and a favorable outcome after surgical resection, the remaining 20% tend to recur due to their aggressive histopathological characteristics (WHO grade II and III). In case of atypical meningiomas (WHO grade II), it is still unknown whether and to which degree an adjuvant radiotherapy after surgical resection is required. This knowledge gap is highlighted by various contradictory findings in recent studies and reviews, which were partly conducted at our institution. A recent study established and validated a DNA-methylation-based classifier for meningiomas. Results revealed two distinct molecular subgroups for the atypical meningioma (intermediate-A and -B). Moreover, it was shown that large proportions of transitional meningiomas (WHO grade I) and anaplastic meningiomas (WHO grade III) could be molecularly reclassified into the two new intermediate meningioma classes. Finally, the established DNA-methylation-based classification outperformed the WHO classification concerning clinical outcome prediction. These findings suggest that previous studies of atypical meningiomas may have investigated rather heterogeneous cohorts, including other meningioma subtypes, leading to undetected biases. Ultimately, this risk of bias can only be avoided by implementing a DNA-methylation-based classifier to ensure accurate tumor subtype identification. The role of radiotherapy for atypical meningiomas can be specifically and correctly assessed by doing this. Identifying potential subsets of tumors that profit from radiotherapy is the primary objective of this project and a major goal to avoid over- and undertreatment.
PD Dr. med. Julius Emmrich
Charité – Universitätsmedizin Berlin, Department of Neurology and Experimental Neurology
Email: julius.emmrich@charite.de
Fields of Research
- Digital Health
- Global Health
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.
PD Dr. med Cornelius Engelmann
Charité – Universitätsmedizin Berlin, Department of Hepatology and Gastroenterology
Email: cornelius.engelmann@charite.de
Fields of Research
- Acute-on-chronic liver failure
- Regeneration
- Senescence
- Cell-Cell interactions mediating organ injury
Project Title
Exploring the Impact of Hepatocyte Senescence on Tissue Injury and Regeneration in Acute-on-Chronic Liver Failure
Project Description
disease with devastating prognosis which develops on the basis of an acute decompensated liver cirrhosis in combination with extrahepatic organ failures. Sudden disease worsening is frequently triggered by bacterial infections or other precipitating events which are known to be more harmful when liver cirrhosis is present but easy to handle in patients without liver disease. This observation suggests an organ sensitisation of the liver being the initiating mechanism for ACLF. In addition, a general lack of tissue regeneration was also linked to patients’ persistent organ dysfunction and poor prognosis. Upon injury hepatocytes may develop a cell cycle arrest, so called cellular senescence, which has the potential to explain both observations. Cellular senescence alters the phenotype and receptor expression of hepatocytes and the ability to proliferate and to replace injured tissue. The main aim of that project will be to explore the mechanistic role of hepatocellular senescence in modulating the course of ACFL and severity. As a first step human liver tissue from patients with different severity grades of end-stage liver disease will be characterised for the expression and activation of regenerative and senescent pathways. Focus will be on the Mdm2-p53 pathway, which is the best-described senescence pathway. TLR4 signalling may triggers senescence and we hypothesis that this is mediated by TGF-β1 which trans-activates the p53 pathway independent of DNA damage or other forms of cellular injury. For both objectives the effect of targeted molecule silencing in vitro (e.g. siRNA) and in vivo (e.g. conditional knockout mice) allows to delineate the relevance of senescence pathways in ACLF. Furthermore we are planning to develop a liver ACLF organoid model to mimic part of the complexity of ACLF in vitro. It will allow to pre-test multiple therapeutic compounds to select those with high likelihood for in vivo efficacy. The last objective will be to test pre-selected senolytic therapies in different ACLF mouse models and to select the most effective agent for translation into humans. Therefore, this project will combine basic with translational science to understand the mechanism of regenerative response in ACLF, to develop new experimental techniques and also to pave the way for a novel treatment for a disease with still devastating prognosis.
Dr. med. Lucia Katharina Feldmann
Charité – Universitätsmedizin Berlin, Department of Neurology and Experimental Neurology
Email: lucia.feldmann@charite.de
Fields of Research
- Parkinson's disease
- Deep Brain Stimulation
- Neuromodulation
Project Title
Towards the Clinical Implementation of Adaptive Neurostimulation: Evaluation of Chronic Electrophysiological Biomarkers
Project Description
Deep brain stimulation (DBS) is an established, effective therapy for movement disorders, improving motor symptoms and restoring a better quality of life. Moreover, the possibility to record electrophysiological activity in the basal ganglia through the implanted DBS electrodes has expanded the pathophysiological understanding of movement disorders. Beta frequency band (13-35 Hz) activity in the subthalamic nucleus (STN) is characteristic for Parkinson’s disease (PD) and a potential biomarker, as activity levels correlate with symptom severity and are modulated through therapy. Adaptive DBS (aDBS) is a concept aiming to provide stimulation titrated to the real-time analysis of biomarker activity. To date, most aDBS studies have been limited to short-term experimental, acute peri-operative settings, and little is known about the validity of beta-band activity as a chronic biomarker. Using the novel Percept neurostimulator (Medtronic, Minneapolis, USA), STN local field potential recordings can now be streamed from chronically implanted DBS electrodes, with the advantage of electrophysiological recordings over long time periods, in freely moving patients, and without acute peri-operative limitations. We hypothesize that beta band activity is a stable, chronic electrophysiological biomarker for longterm application in everyday-life, reflecting motor performance, affective symptoms and therapy effects. In the first study part, a cohort of chronically implanted PD patients (>3 months after DBS surgery) will participate in a monopolar review with stepwise stimulation increase and corresponding motor performance assessments, ON and OFF dopaminergic medication. This allows the evaluation of therapy effects and symptom severity in relation to biomarker activity. In a second step, long-term characteristics of biomarker peak activity will be assessed for two weeks, in relation to factors such as motor activity, mood, therapy changes or circadian rhythms documented in patient diaries and clinical scores. Overall, the results of this study will provide a better understanding of chronic biomarker dynamics. As the Percept neurostimulator also has the potential of aDBS therapy, this study lays the foundation for the implementation of neurophysiological research in therapy optimization, towards the clinical application of personalized adaptive neurostimulation.
Dr. Carina Flemmig
Charité – Universitätsmedizin Berlin, Department of Pediatrics, Division of Oncology and Hematology
Email: carina.flemmig@charite.de
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
Charité – Universitätsmedizin Berlin, Department of Cardiology
Email: julian.friebel@charite.de
Fields of Research
- Protease-activated receptors
- Atherosclerosis
- Heart failure
Project Title
Protease-Activated Receptors in Cardiovascular Thromboinflammation
Project Description
Protease-activated receptors (PARs) regulate platelet, endothelial, and immune cells as well as fibroblast and cardiomyocyte function. PARs are a family of G-protein- coupled receptors (PAR1–PAR4) with a unique activation mechanism via cleavage by the serine proteases of the coagulation cascade, like FXa and FIIa, immune cell-released proteases, and proteases from pathogens. Our group has shown that the tissue factor (TF)/FXa/ thrombin/PARs pathway plays a central role for the innate immune response in the heart during myocarditis. PARs regulate immune response not only by sensing pathogens but also by direct activation of platelets and immune cells, thereby mediating proinflammatory cytokine secretion and chemokine expression. Furthermore, endothelial
PARs activation, stimulates leukocyte adhesion, rolling, and migration. This cascade is initiated by TF. We have recently demonstrated that the treatment with the PAR1 antagonist, vorapaxar, reduced inflammation in a metabolic disease model. Furthermore, we have shown that
PARs are important regulators of adverse extracellular matrix remodelling. Activation of PAR1 and PAR2 is associated with cardiac fibrosis. PAR1 is the most abundant G-protein–coupled receptor in cardiac fibroblasts. We have shown that PAR2 is an important regulator of profibrotic PAR1 signaling and TGF-β-receptor signaling. Targeting the pleiotropic effects of the FXa/FIIa-PAR-axis, which go beyond the anticoagulatory effects of FXa inhibitors, reduced markers of cardiac fibrosis, and diastolic dysfunction in patients with heart failure with preserved ejection fraction (HFpEF). Therefore, intervening in the FXa/FIIa-PAR1/PAR2/TGF-β-axis might be a promising synergistic approach in a selected cohort of patients with HFpEF to reduce cardiac fibrosis and inflammation. Next, we will study the role of PARs during the pathogenesis of atherosclerosis and atrial fibrillation.
Dr. med. Steffen Fuchs, MSc
Charité – Universitätsmedizin Berlin, Department of Pediatrics, Division of Oncology and Hematology
Email: steffen.fuchs@charite.de
Fields of Research
- Neuroblastoma
- Gene Expression Regulation
- Circular RNAs
Project Title
The Role of Circular RNAs in Neuroblastoma
Project Description
Neuroblastoma, an embryonal tumor arising from peripheral sympathetic neuron precursor cells, is the most common extracranial solid tumor of childhood. Approximately half of all children diagnosed with neuroblastoma present with high-risk disease, for which therapeutic options are aggressive and have limited cure rates of at most 40%. No curative therapeutic options currently exist for relapsed neuroblastoma, emphasizing the urgent need for the development of new strategies. Circular RNAs (circRNA) arise by a form of alternative splicing, termed backsplicing, and have recently emerged as a new class of non-coding RNAs important for regulating gene expression. They bind miRNAs or RNA binding proteins via specific sequences to inhibit their function and directly influence transcription. Circular RNAs were recently shown to be highly abundant in neural tissues, especially during development. This makes them particularly interesting for the pathogenesis of neuroblastoma. In this project, we will identify and functionally characterize candidate circRNAs in neuroblastoma. For this purpose, we will establish an RNA Sequencing pipeline to specifically detect circRNAs in neuroblastoma tissue samples covering the whole spectrum of disease. More- over, we will create cell line models that represent the most important genetic alterations in this tumor identity. Identified circRNAs will be validated in vitro in neuroblastoma cell lines and functionally characterized. Ultimately, our aim is to describe functional networks of circRNAs, inhibited miRNAs and downstream oncogenes, tumor suppressors or kinases. In this way, we hope to not only add to the current understanding of neuroblastoma pathogenesis, but also define new druggable targets and associated predictive biomarkers for high-risk disease.
Dr. med. Brigitta Globke
Charité – Universitätsmedizin Berlin, Department of Surgery
Email: brigitta.globke@charite.de
Fields of Research
- Liver Transplantation
- Kidney Transplantation
- Photoplethysmographic Visualization of Tissue Perfusion
Project Title
Intraoperative AR Guided Photoplethysmographic Visualization of Tissue Perfusion
Project Description
The optimal perfusion of kidney grafts is vital for the long-term outcome after kidney transplantation. Perfusion can be infl uenced by the placement of the organ in the retroperitoneal space. Using photoplethysmographic visualization tools, minimal changes in colour, that cannot be detected by the human eye, should be made visible and give an idea about the quality of organ perfusion. In a second step this technology should be made available to the surgeon in the operating room via an augmented reality tool, so an optimal placement of the graft can be achieved in less time and with more security concerning optimal perfusion.
Dr. med. Carl Christoph Goetzke
Charité – Universitätsmedizin Berlin, Department of Pediatric Neurology
Email: carl-christoph.goetzke@charite.de
Fields of Research
- Autoinflammatory diseases
- Autoinflammation
- Proteasome
- Regulation of inflammation
Project Title
Identification of Novel Genetic Mutations Involved in Proteasome-Assosiated Autoinflammatory Syndrome
Project Description
Monogenic autoinflammatory diseases are characterized by an unprovoked overreaction of the immune system including many organs and are characterized by high morbidity and mortality. An example of a very rare autoinflammatory disease is CANDLE syndrome (»chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature«). This is a proteasome associated autoinflammatory syndrome (PRAAS) in which autoinflammation is triggered by a malfunction in the ubiquitin-proteasome system. The aim of my project is to study an index patient with a so far on a genetic level unexplained cause for his CANDLE syndrome as a basic model to identify further components of the ubiquitin-proteasome system that contribute to autoinflammation. Mutations known so far concern the proteasome-core complex or assembly proteins. We hypothesize that mutations in other proteasome- associated genes may also cause CANDLE syndrome. The aim is to further investigate the causes of CANDLE syndrome. This is expected to yield new insights into the regulation of the ubiquitin-proteasome system, which contributes to inflammation, and additional molecular genetic insights into the regulation of the proteasome or discovery of further proteasome system components, which can be used to develop further therapeutic options for PRAAS/CANDLE syndrome.
Dr. med. Nina Görlich
Email: nina.goerlich@charite.de
Fields of Research
- kidney transplantation
- transplant immunology
- biomarker
Project Title
Next generation urine diagnostics and monitoring- urine FACS in urinary tract infection
Project Description
Kidney transplantation is proven to provide the best therapeutic option for end stage renal disease. Urinary tract infections (UTI) remain a major challenge in kidney transplant patients due to immunosuppression and deviant anatomy. With an incidence up to 98%, UTI compose a high disease burden to this specific patient group, accompanied by the constantly present risk of transplant deterioration, failure, and higher rejection probability. In previous projects, we were able to establish urine flow cytometry to analyze urine sediments stained by fluorophore-conjugated monoclonal antibodies. Applying urine flow cytometry, we are capable of investigating urinary immune cell populations and kidney cells (proximal tubular epithelial cells, distal tubular epithelial cells, and podocytes) and, thereby, determining urinary cell signatures for specific disorders. The goal of this interdisciplinary project with DRFZ and other partners is (i) to investigate urine cell signature in UTI and (ii) to establish urine bacteria flow cytometry to determine triggering bacterial populations. One key element is to detect urinary immune cell population shifting, indicating occurrence of UTI before patients develop symptoms and before transplant injury develops. With this approach I intend to redefine the diagnostic criteria of UTI, as they are currently defined by appearance of symptoms, and at this time transplant injury is often already present. One of many significant advantages of flow cytometry is the short time frame in which a diagnosis is made. Determination of bacteria populations causing present UTI in a fast manner entails the opportunity to start targeted antibiotic treatment as soon as possible. In comparison, waiting up for microbiological results of urine cultures often takes days in which patients are treated empirically. This project is realized by immune signature and bacteria analysis of urine samples of kidney transplant patients in a longitudinal setting. Patients will separate over the time course into developing UTI (event population) or absence of UTI (control group). With my findings I hope to contribute to enhancing UTI diagnostics, to prevent kidney transplant damage by UTI and to provide a new diagnostic tool to increase kidney transplant survival.
Dr. med. Julius Grunow
Charité – Universitätsmedizin Berlin, Department of Anesthesiology and Operative Intensive Care medicine
Email: julius.grunow@charite.de
Fields of Research
- Intensive Care Unit acquired Weakness
- Translational Research
- Muscle Homeostasis
Project Title
The Impact of Bioenergetic Failure on Muscular Function in Critically Ill Patients
Project Description
Intensive Care Unit-acquired Weakness (ICUAW) is a clinical diagnosis defined by a reduction in maximal muscle strength, which cannot be explained by anything other than critical illness itself. It can be observed in the majority of critically ill patients and is further characterized by an early onset, rapid muscle atrophy. Short-term as well as long-term mortality and morbidity are significantly increased in patients with ICUAW. In a previous project, we discovered that preservation of muscle mass in critically ill patients is not able to counteract development of weakness and further does not improve recovery within one year after ICU discharge. We further noticed that, while muscle strength fully recovered after ICU discharge, muscle endurance remained impaired. During commencement of our trial we performed neuromuscular electrical stimulation and noticed that patients contractile response was highly variable, declined over time and dependent on the degree of illness. An observation that had been disregarded earlier but also cannot be explained by muscle atrophy. These findings led us to the conclusion that limited muscle
endurance, dissociation of muscle mass and muscle strength as well as variable contractile response to neuromuscular electrical stimulation are most likely caused by a dysfunctional energy supply. Considering mitochondria are the main energy provider for the human body and especially for muscle activity extending beyond short bursts of maximal strength, we hypothesized that impaired mitochondrial function – bioenergetic failure – could be the main culprit leading to the observed phenotype. We therefore aim in a first step to do a thorough characterization of mitochondrial function, mitochondrial biogenesis as well as related pathways and in a
second step correlate our molecular findings to the clinical, metabolic and electrophysiological data in order to identify key mechanisms as possible therapeutic targets.
Dr. med. Lea-Maxie Haag
Charité – Universitätsmedizin Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology
Univ.-Prof. Dr. med. Dr. rer. nat. Ahmed Nabil Hegazy
Charité – Universitätsmedizin Berlin, Medical Department, Division of Gastroenterology, Infectiology and Rheumatology
Email: ahmed.hegazy@charite.de
Fields of Research
- Immunological Memory
- Host‐Microbiota Interactions
- Inflammatory Bowel Disease
Project Title
Deciphering Host-Microbiota Interactions in Inflammatory Bowel Disease
Project Description
The mammalian gastrointestinal tract is the largest organ of the human body beside the skin. It is the organ containing the largest number of immune cells and harbours a large and diverse population of commensal bacteria that exist in a symbiotic relationship with the host. In recent years, it has become increasingly clear that the composition of this gastrointestinal microbiome and its interaction with the host immune system strongly influences the health of the host. One disease complex, in which maladaptation in this host microbial dialogue is involved, is inflammatory bowel disease (IBD). Here, this maladaptation leads to an aberrant immune response in the gut, resulting in recruitment of various lymphoid and myeloid effector cell populations and inflammation of gut tissue. The exact aetiology of IBD remains uncertain, but it is a multifactorial disease that involves a complex interplay between genetic, environmental, microbial, and immune factors. Deciphering the complex interplay between both the genetic and environmental factors and the microbiota, is therefore of great biomedical importance. By combining mouse and human T cell immunology, mucosal immunology and animal models of disease as well as clinical specimens, we aim to identify environmental, microbial, and inflammatory drivers that promote maladaptation and gut tissue inflammation. We use a combination of cutting edge technologies, high through- put culture methods, cell and organoid cultures, physiological mouse models of colitis and analysis of well defined patient cohorts. We specifically aim to uncover new pathways involved in induction and regulation of tissue resident T cells, bacterial interaction and intestinal inflammation that may offer new therapeutic targets in inflammatory diseases such as IBD.
Dr. med. Maria Heinrich
Charité – Universitätsmedizin Berlin, Department of Anesthesiology and Operative Intensive Care Medicine
Email: maria.olbert@charite.de
Fields of Research
- Postoperative Delirium
- Cholinergic Pathways
- Geriatric Anesthesiology
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. Maria Heinrich
Charité – Universitätsmedizin Berlin, Department of Anesthesiology and Intensive Care Medicine
Email: maria.heinrich@charite.de
Fields of Research
- Postoperative Neurocognitive Disorders
Project Title
Multiomics Analysis of Postoperative Neurocognitive Disorders in Older Patients
Project Description
Postoperative delirium (POD) and postoperative neurocognitive disorder (NCD) are common and severe complications after surgery and are associated with increased morbidity, mortality and loss of autonomy. Both POD and NCD can be regarded as complex diseases, as their development is multifactorial, and only hypotheses are currently available regarding their etiology. It is believed, that no single hypothesis can adequately explain the causal relationships of POD and NCD, and that only pathway interactions can describe the complex phenomena. A systematic approach combining genomic, transcriptomic, proteomic and environmental data using pathway analyses in a patient population has not yet been described. Therefore, the aim of this project is to describe biological pathways involved in the development of POD and NCD using multi-omics analysis in a hypothesis generating approach. This project is part of the multicenter prospective observational study BioCog – »Biomarker Development for Postoperative Cognitive Impairment in the Elderly« (Clinicaltrials.gov ID: NCT02265263). 1032 patients ≥ 65 years of age undergoing elective surgery were included. Primary endpoints are the occurrence of POD and NCD. Blood samples were obtained from patients preoperatively, on the fi rst postoperative day, and three months after surgery. Genomic, transcriptomic, as well as miRNA profi ling data were generated using microarray analysis. In addition, proteomic data on selected parameters are available. These data will be analyzed under consideration of the clinical database in a multi-omics approach. A particular benefit of a multi-omics approach is the possibility of integral (longitudinal) analysis, since data beyond the gene level can also be considered. Another crucial advantage of this project is that omics data from the patient collective of interest are available, that regulatory elements can be taken into account by means of miRNA profi ling, and that the clinical database of the study provides comprehensive information on environmental factors. In addition, repeated sampling enables the consideration of temporal factors related to primary endpoints. All DNA, RNA and plasma samples were stored in a biobank, so that further investigations (e.g. methylation patterns, de novo sequencing) are possible. Finally, biological pathways of POD and NCD are to be established. These should provide new hypotheses for follow-up studies on the prevention and treatment of POD and NCD.
Dr. med. Georg Hilfenhaus
Dr. med. Karl Herbert Hillebrandt
Charité - Universitätsmedizin Berlin, Department of Surgery
Email: karl-herbert.hillebrandt@charite.de
Fields of Research
- Regenerative Medicine/Oncology
Project Title
Decellularized Human Liver Slices as a Three-Dimensional Platform to Generate In Vitro Intrahepatic Cholangiocarcinoma
Project Description
Intrahepatic cholangiocarcinoma (iCCA) is the second most common tumor entity of the liver. The only curative treatment options for patients suffering from an iCCA is surgical resection. iCCA show a high rate of intrahepatic recurrence, which was found to be up to 60 %. For patients with recurrence, primary metastatic cancer, lymph node metastasis or R1 resection, chemotherapy or local ablative therapies are the remaining treatment options. Unfortunately, these therapeutic concepts have poor response rates. Considering this there is the need to explore new therapeutic options: In vitro models are essential tools to investigate tumor biology and the effect of certain pharmaceuticals. Despite iCCA cell lines and 2D primary cell cultures gave insights into the biology of these tumors, they have some important drawbacks like the poor translational value due to the artificial culture conditions. New approaches for in vitro studies are the formation of 3D spheroids and organoids. Nevertheless, these approaches have also shown a selection of tumor cells and tumor-organoids still showed differences in mutations-patterns in comparison to native tumor tissue. In a recently published study, the value of decellularized rat lung and liver tissue on the in vitro formation of colorectal metastasis has been described. We hypothesize that decellularized human liver tissue will promote the in vitro tumor formation of iCCA tumors with a better preservation of tumor microenvironment, genetic mutation pattern and therefore will reflect a better clinical correlation for adjuvant treatments in comparison to 2D primary culture and tumor organoids.
Dr. med. Andreas Horn, MD, PhD
Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology
Email: andreas.horn@charite.de
Fields of Research
- Deep Brain Stimulation
- Movement Disorders
- Brain Connectivity
Project Title
Toward a Virtual Patient in Deep Brain Stimulation
Project Description
Deep Brain Stimulation – a highly efficacious treatment option for movement disorders such as Parkinson‘s Disease – is currently undergoing a paradigm-shift from stimulating local target regions toward network stimulation, i.e. neuronal modulation of distributed brain net- works. Specifically, it was long thought that the procedure exerts its therapeutic potential by local modulation of the target region itself. However, accumulating evidence suggests that effects on distributed brain networks and basal-ganglia-cortical loops are at least equally important. Our group published several articles of general network interactions between DBS electrodes and remote sites using electrophysiology and brain imaging. However, recently, in cooperation with Harvard Medical School, we were able to demonstrate that clinical DBS improvment may be predicted using MRI-based brain connectivity estimates between the site of stimulation and distributed cortical areas. In this study, the structural and functional connectivity profiles of DBS electrodes in 95 Parkinson patients from two DBS centers (Berlin & Würzburg) were highly predictive of clinical motor improvement across patients. Moreover, the study defined effective treatment networks for Parkinson‘s Disease that may one day be used to guide programming and targeting of deep brain stimulation after further validation. The technique was introduced for Parkinson‘s Disease but could even be of stronger use in the case of Dystonia, where changes in stimulation parameters often lead to a delayed symptom alleviation and guidance from computer models could be even more helpful in clinical practice. Adopting the technique for treatment in Dystonia is the current focus of our work.
Dr. med. Vanessa Hubertus
Charité – Universitätsmedizin Berlin, Department of Neurosurgery (including Pediatric Neurosurgery)
Email: vanessa.hubertus@charite.de
Fields of Research
- Spinal Cord Injury
- Spinal cord regeneration
- Neuroregeneration
Project Title
Promoting neurovascular regeneration in Spinal Cord Injury via the cell-specific regulation of Ephrin-B2 signaling
Project Description
Traumatic Spinal Cord Injury (SCI) is one of the leading causes of disability in the world. A complex pathophysiology and insufficient endogenous regeneration of the spinal cord leave this condition not accessible to curative therapy. The overarching goal of our research is to facilitate endogenous regeneration to ameliorate spinal cord regeneration post SCI. Experimental research in ischemic stroke, a condition which in its pathophysiology resembles SCI, could show the guidance molecule Ephrin-B2 to be associated with a stabilization of the neurovascular unit (NVU). In SCI, the role of Ephrin-B2 is not well-known and an inhibitory role through the induction of astrogliosis is assumed. With this project, we aim to examine the cell-specific role of Ephrin-B2 on neurovascular regeneration post SCI. We hypothesize that 1st endothelial Ephrin-B2 plays a significant role in stabilizing the NVU post SCI and its specific knock-out leads to an aggravation of secondary injury in the spinal cord. 2nd Ephrin-B2 in reactive astrocytes inhibits axonal regeneration and its specific knock-out ameliorates spinal cord regeneration. To test these hypotheses, a cell-specific conditional knock-out mouse model is utilized (R. Adams, Münster). The primary endpoint of this project is neurological restitution, and the secondary endpoint is structural regeneration of the spinal cord. Methodically, behavioral analysis using Catwalk® automated gait analysis, magnetic resonance imaging, histological and immunohistochemical analyses, and longitudinal in vivo microscopy will be performed. As the current therapy of spinal cord injury is restricted to supportive therapies, the findings of this study will lead to an enhanced understanding of SCI pathophysiology and spinal cord regeneration with the final goal to develop translational therapies building on this preclinical work in the future. This project is performed at the neurosurgical Spinal Cord Injury laboratory at Charité Berlin in cooperation with the Fehlings Laboratory at the Krembil Neuroscience Center, University Health Network, Toronto, Canada.
PD Dr. med. Paul Jahnke
Charité – Universitätsmedizin Berlin, Department of Radiology (including Pediatric Radiology)
Email: paul.jahnke@charite.de
Fields of Research
- 3D printing
- Computed tomography
- Image quality
- Standardization
Project Title
3D Printing of Tumor Models to Standardize Radiomics Biomarkers in Oncologic Patients
Project Description
Radiomics makes quantitative information available from computed tomography (CT) images that provides new diagnostic and prognostic insights into tumor diseases. Novel radiomics biomarkers have shown high potential for better, personalized tumor therapies in numerous studies. However, as the field progresses, the quality of CT data becomes increasingly important. Radiomics features are extracted from tumor pixel information, which currently varies widely across institutions, scanners and even within the same scanner. This situation represents a major limitation for the robustness and clinical application of radiomics. Imaging phantoms are reference objects of known ground truth and represent a standard instrument in testing, controlling and comparing imaging systems. However, standard CT phantoms test and standardize technical system parameters, but do not evaluate radiomics features. Based on a new technology specifically developed for 3D printing of radiopaque objects, our aim is to develop the first reference tumor phantom for radiomics. We will use the phantom to evaluate effects of imaging technologies on the robustness of radiomics features, and we will develop methods to improve the quality of CT data, establish standardization and enable more reliable radiomics analyses.
Cao Zhong Jing Jin
Charité - Universitätsmedizin Berlin, CC08 - Chirurgische Klinik (CVK)
Email: cao.jin@charite.de
Fields of Research
- high-grade pancreatic duct dysplasia
- single-nuclei RNA sequencing
- spatial transcriptomics
Project Title
Deciphering the molecular determinants for the transformation of high-grade pancreatic duct dysplasia to invasive carcinoma by single-cell transcriptomics
Project Description
Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal abdominal cancers in humans. Despite significant progress in understanding the molecular mechanisms during pancreatic carcinogenesis, we still lack effective biomarkers for earlier detection or even targeted therapies. Recent advances in Single Cell Transcriptomics enable analyses of high-resolution RNA profiles on singled cells. These studies mainly focused on PDAC biology, while we predict that the analysis of the premalignant neoplasms may provide more important insights into the process of developing invasive pancreatic carcinoma.
Methods: In this study we analyze fresh-frozen pancreatic tissues harboring carcinoma with concomitant precursor lesions of high-grades and subsequently extract and sort the single nuclei for snRNAseq (single-nuclei RNA Sequencing). The cohort will include 10-12 tissues from 9-10 patients, who underwent resection of the pancreas for worrisome or malignant features. We have established an interdisciplinary workflow that will enable us the generation of high-profile transcriptomic signatures of cellular subpopulations involved in the carcinogenic process. The generated transcriptomic data will be correlated with spatial information using NanoString technologies (GeoMx) of cryosectioned tissue samples.
Preliminary Results: We have prospectively collected fresh frozen pancreatic tissue samples from 122 patients. On the selected samples, we have established and successfully applied an optimized workflow from tissue collection, histological sectioning, RNA extraction with quality assessment to library preparation and snRNA sequencing. Additionally, we were able to generate our first spatial transcriptomic data of representative pancreatic samples by GeoMx analyses, after defining regions of interest (ROI) and staining with cellular markers for subsequent spatial sequencing.
Conclusions: By combining two of the most sensitive and accurate technologies for transcriptional profiling, including snRNAseq and Spatial Transcriptomics, precious unbiased molecular data on rare entities of pancreatic precursor lesions and its neighboring carcinoma, will be obtained. Our particular focus on precursor lesions concomitant with carcinoma (PDAC), likely leads to novel insights into disease-relevant subpopulations and driving signatures (mRNA) during the pancreatic
cancer progression from high-grade to invasive carcinoma.
Dr. Michael Kaczmarczyk
Charité – Universitätsmedizin Berlin, Department of Psychiatry
Email: michael.kaczmarczyk@charite.de
Fields of Research
- Major Depressive Disorder
- Neuroenhancement
Project Title
Effects of Mineralocorticoid Receptor Stimulation on Cognitive Bias and Social Cognition in Patients with Major Depression: What Is the Role of NMDA Receptors?
Project Description
People suffering from major depression often show impaired cognitive function while cortisol secretion is increased. The steroid hormone cortisol is released in response to stress and acts in the central nervous system upon glucocorticoid (GR) and mineralocorticoid receptors (MR). GR are widely distributed across the brain while MR are predominantly expressed in the hippocampus and prefrontal cortex – two brain areas closely related to cognitive function and cortisol secretion. We have shown that fludrocortisone, a mineralocorticoid receptor agonist, improves memory and executive function in depressed patients and healthy controls. Stimulation of MR might have led to an increase of glutamate that acts on glutamatergic NMDA receptors in the hippocampus and prefrontal cortex. However, depressed patients not only exhibit cognitive deficits in traditional neuropsychological domains such as memory or executive function. In addition, there are depression-specific alterations such as cognitive bias and deficits in social cognition, two clinically highly relevant areas. Therefore, the specific aims of our work are two-fold: 1) To examine whether beneficial effects of fludrocortisone in depressed patients can be extended to depression-specific cognitive bias and to social cognition and 2) to determine whether beneficial effects of fludrocortisone depend on NMDA receptor function and whether these beneficial effects can be enhanced by co-administration of the partial NMDA receptor agonist D-cycloserine. Our study not only advances current knowledge by further examining the mechanism of action by which MR stimulation exerts beneficial effects on cognition but extends these effects to depression-specific cognitive bias and alterations in social cognition. Furthermore, a potential interaction between MR and NMDA receptors is highly clinically relevant given the promising results with NMDA receptor antagonists in the treatment of major depression.
Anton Kern
Charité - Universitätsmedizin Berlin, CC17 - Klinik für Pädiatrie m.S. Onkologie und Hämatologie (CVK)
Email: anton.kern@charite.de
Fields of Research
- CAR-T therapy
- pediatric oncology & hematology
- immunology
Project Title
Engineering CAR-T cells with a Fas-4-IBB switch receptor to overcome activation-induced cell death and improve CAR-T cell therapy for neuroblastoma
Project Description
Chimeric antigen receptor T (CAR-T) cell therapy, although highly effective against blood-borne malignancies, has not yet achieved major success in pediatric solid tumors such as neuroblastoma (NB). This is in part related to an immunosuppressive tumor microenvironment (TME) characteristic for solid tumors as well as tumor heterogeneity that frequently result in recurrence of tumor variants that have lost the target antigen . Additionally, the effects of the TME and the strong and repetitive stimulation of CAR-T cells when exposed to the tumor often result in exhaustion and even depletion of CAR-T cells called activation-induced cell death (AICD). Those effects result in lower quality and quantity of administered CAR-T cells limiting the effectiveness of
CAR-T cell therapy. This is especially interesting because clinical data suggests that prolonged persistence of CAR-T cells corelates with clinical outcome. Using more sophisticated CAR-T engineering to overcome AICD and to effectively prolong the survival of CAR-T cells could be the answer to transfer the great results seen in hematologic malignancies to patients with neuroblastoma and maybe even other pediatric solid tumors. My study aims to do so by developing CAR-T cells resistant to Fas-induced cell death, one of the main effector pathways of AICD, to save the strongly activated CAR-T cells from death mediated by the engagement of FasL expressed on T cells, neuroblastoma cells, or immune modulatory cells in the TME. To achieve that goal CAR-T cells will be engineered to express a switch receptor that makes them resistant to FasL-mediated killing by turning the death signal into a costimulatory signal.
Dr. med. Arne Kienzle
Charité – Universitätsmedizin Berlin, Center for Musculoskeletal Surgery
Email: arne.kienzle@charite.de
Fields of Research
- Bone Metabolism
- Joint Infection
- Osteitis
- Arthroplasty
Project Title
Role of Osteitis and Osteomyelitis in Altered Bone Homeostasis in Patients with Periprosthetic Joint Infection
Project Description
Despite increased use of antibiotics and improved aseptic surgical techniques, periprosthetic joint infections (PJI) still occur in 1-5% of primary total knee arthroplasties. In PJI, microorganisms form a biofilm on the implant making the infection highly resistant to antibiotic treatment. Once a biofilm forms on the implant, complete removal of the infected prosthesis and, in most cases, in a second stage surgery, reimplantation of a new prosthesis is necessary. After PJI-dependent revision surgery, we found a drastically elevated risk for prosthesis failure: In this study, 22% of all patients suffered from long-term complication aseptic loosening and 16% from recurrent PJI; suggesting PJI significantly and lastingly alters the bone metabolism. Our research focuses on understanding the altered pathomechanisms involved in this pathology. We hypothesize that the increased risk for aseptic loosening after PJI is due to an inflammatory response in the bone and bone marrow, i.e. osteitis and osteomyelitis. In PJI, adaptive immunological processes potentially impact the regenerative function of osteoblasts and thus disturb the bone and bone marrow homeostasis, subsequently altering bone density and metabolism. Our clinical observations suggest that these changes persist despite guideline compliant anti-microbial and surgical treatment. In this respect, affected patients could benefit from treatments that restore bone homeostasis and counteract osteitis and bone loss. Additionally, profiling patient’s systemic immune competence from peripheral blood samples may help identify patients especially at risk for impaired bone formation and thus consecutive prosthesis failure.
Dr. med. Martin Klatt
Charité – Universitätsmedizin Berlin, Department of Hematology, Oncology and Cancer Immunology
Email: martin.klatt@charite.de
Fields of Research
- Immunotherapy
- Immunopeptidomics
- TCR mimic CAR T cells
Project Title
Mass spectrometry driven identification of T cell immunotherapy targets in head and neck squamous cell carcinoma
Project Description
Even if treated with state-of-the-art care, patients diagnosed with metastatic head and neck squamous cell carcinoma (HNSCC) face a devastating 8 months median overall survival highlighting a profound unmet medical need for additional treatment strategies. Over the last years, immunotherapeutic approaches such as antibody-based immune checkpoint blockade have been implemented successfully in clinical care demonstrating responsiveness of HNSCC towards immunotherapy. This effect might be mediated by T cell recognition of the three different sources for highly tumor-specific immunotherapy targets expressed in HNSCC tumors: oncogenic viral antigens, cancer germline antigens and mutation-derived neoantigens.
We aim to identify these tumor-specific targets, which are presented on the cell surface as small peptides in the context of Human Leukocyte Antigen (HLA) complexes. Utilizing immunoprecipitation of these HLA complexes followed by ultrasensitive mass spectrometry of the presented peptides will enable us to determine their exact amino acid sequences. To increase the sensitivity and clinical relevance of this approach, we will first identify all potentially presented HLA ligands in an overexpression system of COS7 cells transfected with HLA complexes (HLA-A*01, -A*02 or -A*03) and antigens (viral, cancer germline or somatically mutated) of interest. Then, we will validate the presence of such bona fide HLA ligands in tumors generated from patient derived xenograft (PDX) models to ensure their biological relevance.
Such well-defined and validated HLA ligands will then form the basis for future studies in which we aim to identify reactive TCRs as wells as TCR mimic CAR T cells to develop and provide effective cellular immunotherapies for patients with HNSCC.
Dr. med. Felix Kleefeld
Charité – Universitätsmedizin Berlin, Department of Neurology and Experimental Neurology
Email: felix.kleefeld@charite.de
Fields of Research
- myositis
- proteomics
- neuromuscular diseases
Project Title
Moving towards „Myositis 3.0“: Yet another classification?
Project Description
Idiopathic inflammatory myopathies (IIMs) form a group of autoimmune diseases affecting the skeletal muscle and, to a variable extent, other organ systems (e.g. skin, lungs, heart muscle). While research has shown that the pathogenesis of IIMs is heterogeneous, this fact is not reflected by the current classification systems. As a consequence, in many cases the treatment of IIMs follows an "one fits all" approach that does not reflect the complex molecular differences of IIMs. Pilot studies have shown that some subtypes of IIM might even be misclassified in the current diagnostic classifications. In this project, we will perform state-of-the-art untargeted proteomics in a large cohort of patients with IIM to explore the molecular pathogenesis of the different diseases. This data will then be used in the development of a modern, evidence-based classificition system ("Myositis 3.0") that may hold important implications for future therapy strategies (e.g. targeted therapies) in the context of IIMs.
Dr. med. Daniel Kroneberg
Charité – Universitätsmedizin Berlin, Department of Neurology and Experimental Neurology
Email: daniel.kroneberg@charite.de
Fields of Research
- Parkinson’s Disease
- Movement Disorders
- Deep brain stimulation
- Gait assessment
Project Title
Network Modulation for the Improvement of Gait Function in Parkinson’s Disease
Project Description
Disturbances of gait and balance and specifically freezing of gait (FoG) are clinical features of advanced stages of Parkinson’s disease (PD) that are associated with an increased risk of falls, reduced mobility and impaired quality of life. Deep brain stimulation (DBS) of the subthalamic
nucleus (STN) is a highly efficacious treatment for motor symptoms of PD such as tremor, rigidity and bradykinesia but with limited effects on gait disability. Therapeutic effects of DBS relate to modulation of distinct brain networks connected to the stimulation area via basal-ganglia-cortical-pathways. Here, specific structural and functional connectivity patterns have been identified that are associated with and predictive of motor improvement. We will adapt this methodology to study the optimal connectivity profiles of DBS for improving gait function and particularly FoG in Parkinson’s disease. To account for the diversity of gait phenomena in PD, sensor based kinematic measurements will provide high resolution, multi-parametric assessments of gait performance ON and OFF DBS. For each patient, specific profiles of network activation and connectivity will be
modeled from the reconstructed DBS-electrodes based on normative structural and functional connectomes and then related to individual modulation of gait performance. This will clarify if we need to target different networks to treat gait disability in contrast to other motor symptoms of PD. This study aims to optimize DBS therapy towards a more patient- and symptom-oriented approach that may be integrated into future solutions for adaptive DBS.
Dr. med. Anna Kufner
Charité – Universitätsmedizin Berlin, Department of Neurology and Experimental Neurology
Email: anna.kufner@charite.de
Fields of Research
- Ischemic stroke
- Magnetic resonance imaging (MRI)
- Contrast-enhanced MRI
Project Title
Training-Induced Changes in Vascular Morphology and Cerebral Perfusion after Stroke – a Multiparametric MRI Study
Project Description
Early rehabilitation is an essential part of the recommended therapy following an acute cerebrovascular event due to unequivocal evidence that regular physical activity not only mitigates risk factors (i.e. hypertension, dyslipidemia) but also has a beneficial effect on functional recovery following stroke. However the underlying mechanisms of physical activity leading to an improved outcome are poorly understood. Pre-clinical studies from our research group have demonstrated the beneficial effects of exercise on long-term stroke outcome in rodents and have attributed the observed effect to training- induced angiogenesis. Physical activity not only led to a histological increase in microvessel density but also led to visible changes in vessel morphology and ultimately resulted in enhanced cerebral flood flow and better long-term functional recovery in rodents following minor ischemic stroke. In patients, the mechanisms underlying the beneficial effects of exercise following stroke are far less explored. In 2013, our research group designed and initiated the PHYS-STROKE Trial (a Phase III randomized controlled trial [RCT]) – which was the first trial designed to assess the effect of physical activity on functional outcome following stroke. Recent developments in magnetic resonance imaging (MRI) suggest that selected sequences – such as vessel size imaging (VSI) – now allow for an in vivo assessment of cerebral microvasculature in patients. With this novel imaging technique in mind, an exploratory sub-study of the PHYSSTROKE trial was designed called BAPTISe (Biomarkers and perfusion – training induced change after stroke), in which a subgroup of patients receive multiparametric contrast-enhanced MRI before and after intervention (aerobic fitness vs. relaxation). The aim of the current project is to translate our own pre-clinical findings on the effects of exercise on cerebral perfusion and angiogenesis into clinical research with the use of multiparametric, contrast-enhanced MRI. The aim of this project is to assess whether VSI can reliably assess the cerebral microvasculature in-vivo in acute and sub-acute stroke patients. Furthermore, we aim to assess whether physical training will result in changes in MRI-derived microvascular morphology and cerebral perfusion parameters in stroke patients, corresponding to pre-clinical findings and whether these changes can predict stroke outcome.
Dr. med. Cornelia Lachmann (geb. Knaak)
Charité – Universitätsmedizin Berlin, Department of Anesthesiology and Intensive Care Medicine
Email: cornelia.lachmann@charite.de
Fields of Research
- Telemedicine
- Immunology
- Rare Diseases
Project Title
Telemedicine for Quality Improvement in diagnosis and therapy of Hemophagocytic Lymphohistiocytosis
Project Description
Hemophagocytic Lymphohistiocytosis (HLH) is a rare though life-threatening hyperinflammatory syndrome in which uncontrolled immune activation leads to excessive cytokine release - the so-called cytokine storm. Due to its clinical overlap with sepsis, HLH remains frequently undetected. Mortality rates are high, particularly among critically ill patients (58 %). In a previous systematic review, we could demonstrate that a multitude of therapeutic strategies are applied in HLH patients while current recommendations remain inadequately implemented. Here, telemedicine offers a unique opportunity for research while at the same time improving diagnosis and therapy of HLH. Within this project, we will establish a reference center for national and international consultation requests. In that we concentrate digitally all HLH cases in one center, we will generate a sufficient number of cases to perform robust data analysis. Diagnosis and therapy recommendations are based on current guidelines. For therapy evaluation, daily telemedical visits are carried out from the day of the first consultation. Serious and refractory cases are assessed interdisciplinary by a Charité expert panel.
Moreover, there is an unmet need of targeted therapies. One reason lies in the poorly investigated pathophysiology of HLH. Therefore, we will establish and expand a biobank of cytokine profiles to enable safe diagnosis and causal treatment.
Collecting data of a rare disease prospectively will allow us to create a machine learning algorithm which will ultimately support deep disease characterization. The database will be used to develop an app for physicians as a diagnostic and treatment tool. Simultaneously, data will be transmitted via the app for scientific evaluation.
Our aim is to reduce in hospital mortality through rigorous adherence to current guidelines. Moreover, we will assess treatment efficacy and develop an HLH severity score to improve classification of HLH patients. This project is the first international study in HLH patients using telemedicine.
Dr. med. Alena Laschtowitz
Charité – Universitätsmedizin Berlin, Department of Hepatology and Gastroenterology
Email: alena.laschtowitz@charite.de
Fields of Research
- Hepatology
- Immunology
- Bioinformatics
- Next Generation Sequencing
Project Title
Deciphering the inflammatory microenvironment in fatty liver disease on a single cell level by snRNAseq analysis
Project Description
Non-alcoholic fatty liver disease (NAFLD) is a chronic inflammatory liver disease that represents the leading cause of chronic liver diseases worldwide. Without intervention, NAFL may progress to its inflammatory form, non-alcoholic steatohepatitis (NASH), with an increased risk of cirrhosis and hepatocellular carcinoma development. While numerous novel pharmacotherapeuticals have been tested in clinical trials, most have failed to deliver the desired outcomes of steatohepatitis resolution or reversal of fibrosis. The early identification of patients at risk for disease progression is an unmet need while disease-specific mechanisms that drive chronic inflammation in NASH are still enigmatic.
Single cell RNA-seq techniques are indispensable for an unbiased approach for the study of gene expression but are challenging in the liver due to its complex cell composition. In our collaborative project we will apply the innovative method of single nuclei RNA-sequencing to decipher the inflammatory microenvironment on a single cell level in routinely performed liver biopsies of patients developing NASH, to identify possible new treatment targets. By identification of novel non-invasive biomarkers and implementation of machine learning techniques we strive to develop diagnostic and prognostic tools to identify patients at risk for disease progression.
Dr. med. Roxanne Lofredi
Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology
Email: roxanne.lofredi@charite.de
Project Title
Network Modulation of Motor Inhibition in Parkinson’s Disease
Project Description
Subthalamic deep brain stimulation (DBS) is a well-established and effective treatment option for patients with Parkinson’s disease (PD) leading to better motor performance and quality of life. A common side effect of dopaminergic medication consists in involuntary movements, so-called dyskinesia. Dyskinesia can also be evoked by high stimulation intensities and lesioning of the subthalamic nucleus (STN). Taken together, these observations suggest a major role of the STN in motor inhibition, with special emphasis on control of involuntary movements. In this study, we will investigate the neuronal network of motor inhibition in PD patients and its modulation by subthalamic DBS. We hypothesize that subthalamic DBS facilitates the initiation of voluntary movements while impeding their termination. This may rely on the modulation of an inhibitory network between the STN and other brain regions that depends on the exact connectivity profile at the DBS-electrode position. With the help of a behavioural paradigm that a cohort of PD patients with subthalamic DBS will perform ON and OFF stimulation, the differential effect of DBS on movement termination will be quantified across patients. In a second step, the patient-specific connectivity profile of DBS-electrode localization will be reconstructed and related to the DBS related effect on movement termination. The results of this study can be integrated in a broader goal of developing a personalized DBS with optimal efficacy / side effects profile. With a similar
approach, a previous study of our group was able to predict a »sweet spot« for DBS with best clinical outcome. The localization of an important motor side effect of DBS would further refine this optimal stimulation spot. Given that new types of DBS electrodes allow a precise and directional current steering, this may lead to a direct clinical benefit for patients with subthalamic DBS.
Dr. med. Jana Lücht
Charité – Universitätsmedizin Berlin, Department of Pediatric Cardiology and Congenital Heart Disease
Email: jluecht@dhzb.de
Fields of Research
- Translational Medicine
- Pediatric Cardiology
- Inflammation
Project Title
Cold Inducible RNA-Binding Protein (CIRBP) as a Diagnostic Marker in Pediatric Cardiac Surgery
Project Description
Both inflammatory reactions and capillary leak syndrome are frequent complications after open-heart surgeries in children with congenital heart disease. Capillary leak syndrome is primarily induced by endothelial dysfunction and is characterized by intravasal volume- and protein depletion, as well as edema. Inflammatory reactions and capillary leak syndrome crucially influence postoperative morbidity as they are associated with a longer stay on the pediatric intensive care unit, prolonged mechanical ventilation and higher demands for catecholamines and sedative medication. To date, only a few risk factors have been identified for the development of inflammatory reactions and capillary leak syndrome. However, we are still lacking suitable biomarkers, which can be used to detect and treat patients at risk early on. Cold inducible RNA binding protein (CIRBP) belongs to the family of coldshock proteins and has been identified as a potent inflammatory mediator. So far, basic research and clinical studies indicate that CIRBP may be of both diagnostic and therapeutic use for inflammatory reactions. Furthermore, experimental studies have shown that CIRBP is involved in the pathogenesis of endothelial dysfunction. As there have been no studies analyzing CIRBP concentrations in peripheral blood after cardiac surgery in children with congenital heart disease, the present pilot study is designed to evaluate CIRBP as a potential diagnostic marker in this cohort. Therefore, patients up to the age of 18 years undergoing a corrective or palliative cardiac surgery at our center will be recruited for the study. Blood samples will be collected directly before and during the first 24 hours after operation at defined time points. In addition to analyzing CIRBP, proinflammatory cytokines, and markers for endothelial dysfunction, serum samples will be incubated with human monocytes (THP-1) and endothelial cells (HUVECs) in the experimental part of the study to analyze induced mechanisms on a cellular level.
Julia Macos
Charité-Universitätsmedizin Berlin, Klinik für Pädiatrie m.S. Onkologie und Hämatologie (CVK)
Email: julia.macos@charite.de
Fields of Research
- pediatric oncology
- solid tumor microenvironment
- CAR T cell therapy
Project Title
Evaluating the effect of intra-tumoral cytokine secretion after tumor microenvironment gene therapy on CAR T cell therapy
Project Description
Therapy-resistant solid tumors represent a growing global challenge. Neuroblastomas are examples of solid tumors and as the most common extracranial solid tumor of childhood responsible for 15% of childhood cancer-related deaths. The overall survival for high-risk cases is still not exceeding 50% and treatment options are limited in cases of relapse. One novel approach could be adoptive T cell therapy with chimeric antigen receptor (CAR) T cells. Response rates in CAR T cell treatment of solid tumors are not yet sufficient due to a series of hurdles, especially insufficient T cell infiltration and an immunosuppressive tumor microenvironment as present in neuroblastoma. While much effort is being put into engineering T cells, striving to tackle the aforementioned limitations and improve response rates this study wants to develop a gene therapeutic approach that alters the tumor microenvironment in a way that T cell and CAR T cell infiltration is increased, and immunosuppression is reduced.
The aim of the group is to develop a CRISPR/Cas targeted cytokine gene therapy to overcome the hurdles of an immunosuppressive tumor microenvironment and to facilitate CAR T cell therapy in solid tumors. The approach aims to modify neuroblastoma cells by CRISPR/Cas9 technology to express transgenes that encode for T cell-attracting chemokines or T cell-stimulating cytokines. Their secretion within the tumor will improve CAR T cell infiltration and efficacy. After in vitro proof of concept for the targeted CRISPR transgene knock-in has been obtained in neuroblastoma cell lines the project will now focus on the evaluation of the effector arm of the proposed gene therapeutic approach that is the multi-modal evaluation of the cytokine effects on neuroblastoma directed CAR T cell therapy in vitro and in vivo.
Dr. med. Tina Mainka-Frey
Charité – Universitätsmedizin Berlin, Department of Neurology and Experimental Neurology
Email: tina.mainka@charite.de
Fields of Research
- Movement Disorders
- Pain
Project Title
Study of the Pathophysiology of Pain in Dystonia by Neurophysiological and Imaging Methods
Project Description
dystonia in up to 75% of patients. It might occur as the first symptom of the disease and oftentimes becomes chronic. For many patients, pain is more disabling than the sustained or intermittent muscle contractions causing abnormal movement and/ or postures which is the main motor manifestation of dystonia. Despite its severe impact on the patients’ quality of life and the significant socioeconomic implications, the phenotype and the pathophysiology of pain in dystonia are mostly unknown. There is no correlation between motor symptoms and pain, and non-dystonic muscles might also be painful. Therapeutic interventions that might relief pain (e.g., injections of botulinum toxin, deep brain stimulation) do not always improve motor symptoms and vice versa. We can therefore assume, that pain in dystonia is not solely generated by dystonic muscles. Recently, it has been proposed that an insufficient descending pain inhibitory system, assessed by conditioned pain modulation, might contribute to pain in dystonic patients. With this project, we aim to phenotype the pain syndrome in large cohorts of patients with various forms of focal and generalized dystonia without and during therapy by means of questionnaires, neurophysiological markers, particularly conditioned pain modulation, and imaging methods. The results will lead to a better understanding of the pathophysiological mechanisms of pain in dystonic syndromes and create a foundation for individualized, mechanism-based therapies.
Dr. med. Tazio Maleitzke
Charité – Universitätsmedizin Berlin, Center for Musculoskeletal Surgery
Email: tazio.maleitzke@charite.de
Fields of Research
- Osteoarthritis
- Cell-based Therapies
- Mesenchymal Stromal Cells
Project Title
MORCA – Mechanism of Regenerative Cell Action
Project Description
Osteoarthritis (OA) is the most common degenerative joint disease worldwide with a marked prevalence increase over the past decades. Primary OA is caused and characterized by a vicious cycle of micro-trauma to the cartilage and a low-grade articular inflammation, that cause chronic pain and functional disability in affected patients. Symptomatic OA treatment comprises lifestyle changes, physiotherapy and analgesia, which unfortunately cannot effectively slow down or halt disease progression. Due to the progressive nature of the disease, arthroplasty is often the only therapy that can replace, yet not restore joint integrity. Placental expanded (PLX) cells are placenta-derived mesenchymal like adherent stromal cells, that are known to exert unique immunomodulatory and regenerative properties in the treatment of muscle injury and critical limb ischemia. Administered locally, PLX cells are able to regulate the adaptive immune response and the pro-inflammatory cytokine distribution. Infiltration of the synovium and the synovial fluid with cells from the adaptive immune system and pro-inflammatory cytokines are key pathomechanisms
of OA, yet PLX cells have not been exploited for intraarticular treatment of OA. With the MORCA project we strive to better understand molecular pathways by which regenerative cells including PLX cells may alter disease activity in a pre-clinical naturally occurring in vivo model of OA (Dunkin Hartley guinea pig model). Potential immunomodulatory and regenerative effects of intraarticular injections of PLX cells will be traced histologically and radiologically as well as through molecular and single cell analyses. To compare pre-clinical results with clinical reality, human OA cartilage and synovium samples will be obtained and included in the analyses. We hope to better comprehend, establish and advance novel regenerative treatment strategies for OA through the work conducted during the Clinician Scientist fellowship. A paradigm shift from a symptomatic to a disease modifying treatment approach for primary OA would have a lasting impact on affected generations to come.
Ellen Meister
Charité-Universitätsmedizin Berlin, Klinik für Radioonkologie und Strahlentherapie (CVK)
Email: ellen.meister@yale.edu
Fields of Research
- Radiology
- Oncology
Project Title
Targeted Immunotherapy in Combination with pH Modulation in a VX2 Rabbit Liver Tumor Model
Project Description
Hepatocellular carcinoma (HCC) represents the most common liver cancer and the second leading cause of cancer-related mortality worldwide. In recent years, systemic immunotherapy has emerged as a promising treatment option for HCC, particularly in advanced stages of the disease.
To maximize the potential of immunotherapy treatment, new methods concerning its application need to be developed. Combining immunotherapeutic agents with locoregional techniques of drug delivery and embolization is hypothesized to significantly enhance treatment success.
This project aims to establish a novel intra-arterial delivery method for immunotherapy in HCC. Locoregional delivery is presumed to improve diffusion of the antibodies within the tumor and its microenvironment, therefore increasing target binding. Localized application of the treatment is expected to minimize off-target inflammation, representing a common side effect of systemic immunotherapy. To increase the expected anti-tumor effect of immunotherapy even further, this study intends to combine checkpoint inhibition with bicarbonate treatment, which has recently been proven successful in elevating the pH in the tumor and its microenvironment, therefore counteracting the immunosuppression caused by the increased output of lactate by the tumor. A combined treatment approach including bicarbonate as well as immunotherapy is expected to enable the most substantial antitumor inflammatory reaction, correlating with a maximized treatment success.
To verify this hypothesis, this study investigates the effect of locoregional immunotherapy in HCC by assigning 12 VX2 liver tumor-bearing rabbits to four treatment arms. These include sham treatment, bicarbonate treatment, immunotherapy, and the combination of both bicarbonate and immunotherapy. All treatments are infused directly into the tumor-feeding artery, followed by a transarterial embolization to prevent washout. The immune cell infiltration into the tumor and its microenvironment is evaluated after seven days using immunohistochemical staining, immunofluorescence, and flow cytometry.
Dr. med. Jochen Michely
Charité – Universitätsmedizin Berlin, Department of Psychiatry and Neurosciences
Email: jochen.michely@charite.de
Fields of Research
- Computational Psychiatry
- Cognitive Neuroscience
- Psychopharmacology
- Neuroimaging
Project Title
Towards a Computational Account of Ketamine’s Antidepressant Effect
Project Description
With an estimated 350 million people affected globally, depression represents one of society’s most challenging and costly health burdens. Traditional pharmacotherapy of depression increases brain levels of monoaminergic neurotransmitters, such as serotonin. However, effects of monoaminergic antidepressants are often modest, and benefits emerge slowly, over a time course of weeks. Recently, an NMDA receptor antagonist, ketamine, was found to improve mood in severe, treatment-resistant depression. Unlike traditional therapy, ketamine acts rapidly, producing antidepressant effects within hours of application. Moreover, ketamine targets glutamate neurotransmission, rather than impacting brain monoamine levels. Consequently, the serendipitous discovery of this novel, rapid-acting antidepressant is hailed as one of the most important advances of modern psychiatry. However, despite ketamine’s promising clinical impact, the mechanisms through which it may work remain elusive. To utilise the enormous therapeutic potential of ketamine, we require a better mechanistic, neuroscientifically grounded, understanding of its effect
on brain function. In this project, I will use cognitive assessment, brain scanning and mathematical modelling, in patients undergoing ketamine treatment. Over the course of the study, patients will be repeatedly tasked on a bespoke decision-making task that I have recently validated in a similar pharmacological study (Michely et al., 2020, Nat Commun). This gamified computer task enables a precise assessment of how patients learn from, and emotionally respond to, rewarding experience. Additionally, I will use non-invasive, functional magnetic resonance imaging (fMRI), allowing me to probe activation of brain circuits involved in human reward processing. Building on a computational psychiatry approach, I aim to decipher the cognitive mechanisms that give rise to ketamine’s antidepressant effect, and identify neurocomputational markers for a clinical response to intervention. Informed by a deeper understanding of the neurobiology of depression and its treatment, my goal is to improve tailoring of currently available, and development of novel antidepressant therapies in the future.
Dr. med. Mirja Mittermaier
Charité – Universitätsmedizin Berlin, Department of Infectious Diseases and Respiratory Medicine
Email: mirja.mittermaier@charite.de
Fields of Research
- Deep Learning
- Viral Pathogenesis
- Explainable Deep Learning
- Human Lung Tissue
Project Title
Explainable Deep Learning to Investigate Viral Pathogenesis in the Human Lung
Project Description
Understanding viral pathogenesis is a key fi eld of investigation in emerging respiratory viruses. It is crucial to gain a deep understanding of the molecular and cellular interplay between viruses and their host to enable innovative adjunctive therapies beyond pathogen-directed clinical approaches. To understand the pathogenesis of a viral infection, it is pivotal to identify the i.) cell tropism (which cells are infected by the virus), along with ii.) other cell types present in the lung tissue and involved in the immune response. Over the past decade, the fi eld of systems virology has evolved and technologies such as microarrays and single cell sequencing provide detailed information e.g. about gene expression signatures. Although those methods provide insights into global responses, they lack the ability to provide spatial context. The other way round, imaging techniques, such as immunohistochemistry, are giving spatial context by detecting cell types and viruses in infected tissue but are limited by the number of labels per sample. In recent years, advanced microscopy imaging techniques signifi cantly improved our understanding of viral pathogenesis. In parallel, deep learning models in image classifi cation showed ground-breaking success on general images and have successfully contributed to solve classifi cation tasks in medical imaging. However, neural networks act like a black box and do not provide any information about what led to the classifi cation decisions. Yet, understanding the algorithms decisions would help to gain profund information and to ensure reproducibility. Although both technologies show major contributions independently, they have not yet been combined to investigate virus pathogenesis. Thus, we aim to develop deep learning algorithms and apply explainable deep learning to analyze »omics-data« along with spatially resolved high-resolution microscopy images to enhance our understanding of viral pathogenesis in the human lung.
Dr. med. Simon Moosburner
Charité – Universitätsmedizin Berlin, Department of Surgery
Email: simon.moosburner@charite.de
Fields of Research
- Liver Transplantation
- Extended Criteria Donor Organs
- Proteomics
Project Title
Extracorporeal Evaluation of Liver Grafts from Older Donors
Project Description
Liver transplantation is the treatment of choice for patients with advanced liver cirrhosis, hepatocellular carcinoma within Milan-criteria, and severe metabolic or autoimmune hepatic disorders. However, the number of patients waiting for liver transplantation exceeds the number of available organs. Notably, in Germany, the success of liver transplantation has been limited by a dramatic decline in organ donation over the last decade. To alleviate the supply and demand imbalance, an increasing proportion of grafts meeting so called extended donor criteria (i.e. high donor age or macrovesicular steatosis hepatis) are accepted for transplantation. These extended criteria donor organs are usually discarded due to a higher susceptibility for ischemia reperfusion injury (IRI), which associated with an increased rate of primary non-function and early allograft
dysfunction. IRI is initiated during warm reperfusion of livers in situ after static cold storage, which remains the current standard of care. A recent alternative to static cold storage is normothermic ex vivo liver machine perfusion (NEVLP): livers are perfused with an oxygenated medium to achieve an almost physiological milieu prior to transplantation. NEVLP enables 1) reduced IR, 2) organ evaluation and characterization prior to transplantation, 3) optimized transplantation logistics, 4) potential for metabolic conditioning during perfusion. Ex vivo machine perfusion therefore has the potential to increase the pool of available organs for transplantation. Currently, around 15% of potential liver grafts are declined in Germany due to donor age or morbidity. Indeed, this problem exists worldwide with similarly high decline rates in the United States with 13%. However, it still remains unclear why some organs from older age donors perform better after transplantation than others. The aim of the project EvALT (Extracorporeal Evaluation of Liver Grafts from older Donors) is therefore to characterize older donor organs during NEVLP using a previously developed small animal model for NEVLP and possibly identifying therapeutic targets for future graft optimization prior to transplantation.
Dr. med. Jawed Nawabi
Charité – Universitätsmedizin Berlin, Department of Radiology (including Pediatric Radiology)
Email: jawed.nawabi@charite.de
Fields of Research
- Stroke Imaging
- Computed Tomography
- Quantitative Imaging
- Outcome Prediction
Project Title
Radiomics Based Machine Learning Prediction of Clinical Outcome on Intracerebral Hemorrhage
Project Description
Intracerebral hemorrhage (ICH) is the most severe form of stroke and remains a major cause of morbidity and mortality worldwide. Early detection of high-risk patients remains a key goal in directing the management and treatment course. Cerebral injury secondary to ICH is a known factor to potentiate the risk of a poor outcome. Rapid advances in our understanding of the underlying mechanisms have fueled an interest in identifying novel therapies targeting secondary injury. However, standardized biomarkers for imaging quantification could so far not be established. Emerging data suggest perihematomal edema (PHE) as a promising biomarker as the temporal course of PHE correlates with the manifestation of secondary injury but results remain inconsistent. Edema formation comprises multiple coordinated and complex mechanisms that are known to be disease-specific. In line with this, the applicant’s previously published work highlights the promising prognostic value of early edema formation in different forms of ICH. The assumption therefore seems reasonable that perihematomal edema holds additional imaging characteristics that are not visible to the human eye, yet of great prognostic value. Progressive machine learning (ML) algorithms have paved the way for a fully automated radiomics analysis and therefore hold a clear clinical impact. The application of ML algorithms for the prediction of clinical outcome after ICH are still lacking and have not included PHE features. The applicant’s previous results demonstrate that radiomic features provide a high discriminatory power in predicting neoplastic ICH on CT, with significantly higher power than human prediction. Quantitative features of PHE in ICH may distill multiple-but-subtle variations such as in thrombin accumulation, influx of inflammatory mediators, and erythrocyte lysis with significant prognostic value. Following this idea, the clinical research project aims at understanding the high-end quantitative imaging characteristics of perihematomal edema (PHE) which may serve as a predictor of poor prognosis and examine the efficacy in predicting patient outcomes after ICH.
Dr. med. Mir Timo Zadegh Nazari-Shafti
German Heart Center Berlin, Department of Cardiothoracic and Vascular Surgery
Email: nazari@dhzb.de
Fields of Research
- Temlomere Biology
- Mesenchymal Stem Cells
- Cardiac Regeneration
Project Title
Search for Markers that Can Predict Efficacy of Autologous Stem Cell Therapy in Cardiovascular Disease
Project Description
For regeneration of the damaged heart, autologous MSC transplantation may be a promising alternative or additional treatment option for successfully augmenting the limited regenerative capacity of the adult heart. While preclinical data supported this hypothesis, data from various clinical studies have proven to be less conclusive on the clinical outcomes after autologous MSC- transplantation. Cellular aging and dysfunction in MSCs from donors with severe chronic disease and elderly donors may be responsible for the under-performance of these regenerative cells in certain subjects during the aforementioned clinical trials. Cellular aging and associated cellular dysfunction is caused by multiple factors and may be assessed by the extent of telomere shorten- ing and dysfunction. Investigating and characterizing the telomere biology of MSCs from a larger patient pool with chronic co-morbidities and correlating them to stem cell function in vitro and in vivo as well as to the donor’s medical history may produce more than just one parameter that could predict the clinical outcome of autologous MSC transplantation for cardiovascular regeneration. The aim of this study is to identify predictive markers that would allow estimating the efficacy and success of autologous mesenchymal stem cell therapy for cardiovascular regeneration before administering the stem cells.
Dr. med., M. Chem. Christopher Neumann
Charité – Universitätsmedizin Berlin, Department of Hematology, Oncology and Cancer Immunology
Email: christopher.neumann@charite.de
Fields of Research
- Pancreatic cancer
- Organoid cultures
- Personalised therapies
Project Title
Potential of Organoid Cultures to Predict the Therapeutic Response in Patients
Project Description
Pancreatic cancer is a highly malignant tumor with a dismal prognosis. Non-specific symptoms, rapid progress, a high rate of metastasis and very little progress in treatment options result in a five-year survival rate of less than 10% with the only curative treatment to be the surgical resection of the tumor. Pancreatic cancer is expected to be the second deadliest cancer by 2030. Once metastasised the treatment is purely palliative. Only very few chemotherapeutic regimes can be administered. None of them taking into account the specific metastatic patterns patients present. Previous results of the CONKO-01 and -05 study group, however, were able to show a significantly prolonged overall survival of isolated pulmonary metastasis after initial surgical resection compared to isolated hepatic metastasis (30,4 vs. 18,1 months) representing a differential physiology of the tumor. Consequently, possible subgroups of the metastatic stage might benefit from more personalised treatment options. By establishing and analysing patient derived organoid models not only from the primary tumor but also from the different metastatic sides, the tumor physiology as a whole can be understood more thoroughly. The aim of this project is to expose patient derived tumor organoids of the primary and metastatic sides to various targeted and well-known chemotherapies and to use proteomics to classify subgroups and identify potential biomarkers of the tumor. By correlating the in-vitro data to
the clinical response rate of these patients, the organoid model can be evaluated as to whether more personalised therapeutic approaches can become future clinical practice.
Dr. med. Christian Oeing
Charité – Universitätsmedizin Berlin, Department of Internal Medicine and Cardiology
Email: christian.oeing@charite.de
Fields of Research
- Basic Science
- Heart Failure
- Autophagy
- Metabolism
Project Title
Fine-Tuning the TSC2-MTOR Axis in Diabetic Cardiomyopathy
Project Description
Diabetes mellitus (DM) is linked with heart failure even after controlling for coronary artery disease and hypertension. This type of heart failure is called diabetic cardiomyopathy (DM-CMP). DM-CMP has become an increasingly recognized entity among clinicians, hence a better understanding of its pathophysiology is necessary for diagnosis and treatment strategies. In this project we address the relevance of a novel phospho-site S1365 on TSC2 in DM. In several murine DM models mTOR is known to be hyperactivated. Our mouse model (S1365A and S1365E knock-in) can potentially alter mTOR signalling in the diabetic heart and change disease course via several mechanisms including metabolic substrate shift and altered autophagic flux. This discovery has not only implications
beyond the cardiomyocyte and the heart but it also reveals a novel mechanism by which PKG works as a strong and drugable command point.
Dr. med. Burcin Özdirik
Email: burcin.oezdirik@charite.de
Fields of Research
- gastrointestinal oncology
- neuroendocrine tumors
- autoimmune liver diseases
Project Title
Multiomics and functional characterization of the mutational landscape in small intestinal neuroendocrine tumors
Project Description
The intestinal epithelium is characterized by rapid self-renewal, driven by crypt-base stem cells that express the R-spondin receptor Lgr5. Stem cell turnover and differentiation into various intestinal cell types have been recapitulated using organoids and, recently, also growth factor conditions to culture hormone-producing enteroendocrine cells (EECs) have been revealed. Characterized by a high level of complexity, EECs can dedifferentiate and form intestinal neuroendocrine neoplasms (NENs), a set of rare but lethal tumors with a concerning increase in incidence. Small intestine neuroendocrine tumors (siNETs) in most cases already present with metastases at the time of initial diagnosis. Their grading is mainly based on the Ki-67 proliferation index, which determines therapeutic procedure and ultimately patient survival. At present, the development of more effective therapies and prognostic markers has been limited partly by a lack of studies aiming to understand the biology of these rare tumors. In addition to small patient numbers, the absence of in vitro and in vivo models that accurately represent these tumors constitute a limitation in this field. To gain a deeper understanding of siNET biology, our group has launched a multiomics project, in which whole genome sequencing (WGS) and transcriptome analysis has been performed. Our preliminary data hint towards an important role of specific mutations. By using organoid culture system technologies, this study aims to understand the functional impact of specific mutations in siNETs and to explore their role for EEC survival, proliferation and dissemination.
Dr. med. Moritz Peiseler
Charité – Universitätsmedizin Berlin, Department of Hepatology and Gastroenterology
Email: moritz.peiseler@charite.de
Fields of Research
- Immunology
- Innate Immunity
- Hepatology
Project Title
In Depth Phenotyping and Functional Profiling of Macrophage Subsets in Chronic Liver Injury and Regression
Project Description
The liver is an important immune organ and provides the critical filter to prevent dissemination of blood-borne pathogens. The filter function is mediated by specialized liver macrophages, Kupffer cells, that are embryonically derived tissue resident macrophages. Kupffer cells have a unique intravascular location and an arsenal of specialized receptors to capture pathogens under fl ow conditions. Furthermore, as intrahepatic sentinels, Kupffer cells initiate or suppress immunity in the liver via crosstalk with many other resident and infiltrating immune cells. Liver inflammation leads to a sustained influx of monocyte-derived macrophages that augment the pool of liver macrophages. These bone marrow-derived cells infiltrate as pro-inflammatory cells fueling liver inflammation or as cells with a repair phenotype. To date, the functional consequence of this macrophage heterogeneity and the fate of different macrophage subsets in chronic liver disease is enigmatic. Since patients with chronic liver diseases are hallmarked with immune dysregulation,
inefficient pathogen clearance on the one hand and exaggerated immune responses on the other
hand, understanding the contribution of different macrophage subsets in the liver is of critical importance. Using a combination of novel linage-tracing tools with state-of-the-art intravital microscopy, we plan to investigate the fate and function of different macrophage subsets in liver disease models. Genetic fate mapping will allow us to differentiate bona fi de Kupffer cells from monocyte-derived macrophages. By using multicolor intravital microscopy, we can investigate the function of these subsets with regards to their critical function: capturing of blood-borne pathogens and initiating / suppressing immune responses in the liver via crosstalk with other cells. These investigations will be complemented by using 25-color spectral flow cytometry to further phenotype the different macrophage populations identified. In addition, as a translational approach, we will investigate liver biopsies of patients with various chronic liver diseases. We will isolate and phenotype liver macrophages with multicolor flow cytometry and correlate the findings with clinical characteristics to better understand macrophage biology in humans. Ultimately, by gaining a better understanding of the functional consequences of liver macrophage heterogeneity, we hope to identify novel pathways that can the targeted therapeutically in patients.
Dr. med. Lennart Pfannkuch
Email: lennart.pfannkuch@charite.de
Fields of Research
- Innate Immunity
- Pneumonia
- Signal transduction
Project Title
The sweetness of infection - the role of a bacterial sugar and a novel pattern recognition receptor in pulmonary inflamm
Project Description
The first line of defence that recognizes a potential pathogen and initiates an inflammatory response is the innate immune system. It depends on a network of specific immune receptors, termed pattern recognition receptors (PRR), that detect bacterial pathogen associated molecular patterns (PAMPs) and initiate a stereotyped immune response. Recently this cellular pathogen recognition apparatus was extended by the discovery of a novel PAMP in Gram-negative bacteria, ADP-heptose (ADP-hep) and its corresponding PRR, Alpha kinase 1 (ALPK1). ADP-hep is a soluble intermediate metabolite in synthesis of the conserved core oligosaccharide of Lipopolysaccharide (LPS) which is an integral component of the outer membrane of Gram-negative bacteria. Binding of ADP-hep to ALPK1 leads to activation of the central immune regulatory transcription factor NF-kB. Involvement of this pathway in initiation of inflammatory responses in vitro could be demonstrated for infections in a growing number of Gram-negative bacteria.
The lung is particularly dependent on a tightly regulated innate immune response that effectively clears an infection and simultaneously conserves organ function. Infections of the respiratory track and especially pneumonia still pose a major medical challenge and are associated with high mortality rates. Especially in hospitalized patients and immunocompromised individuals, infections are frequently caused by Gram-negative bacteria and here antibiotic resistance is becoming more prevalent. So, there is an urgent need to develop novel strategies to improve treatment of infections and to prevent detrimental, de-regulated hyperinflammation. Here, modulation of innate immune responses has been identified as a promising target.
Our aim is to understand the (patho-)physiological function of ADP-hep and ALPK1 in inflammatory responses and development of pneumonia in vivo. This will be tested using a lung infection model with the clinically highly relevant pathogen Pseudomonas aeruginosa.
PD Dr. med. Constanze Pfitzer
German Heart Center Berlin, Department of Congenital Heart Disease, Pediatric Cardiology
Email: pfitzer@dhzb.de
Fields of Research
- Neurological Outcome of Children and Grown‐Ups with Congenital Heart Disease
- Hypothermia
Project Title
»Of Heart and Mind«: A Longitudinal Neuropsychological Evaluation of Children with Congenital Heart Disease
Project Description
Neurodevelopmental deficits are the most common, and potentially most disabling long-term complications for patients with congenital heart disease (CHD) and their treatment. However, only a few studies have investigated the development of the child longitudinally. That is why we would like to test these patients using different neurological and developmental tests. This prospective longitudinal study evaluates the neuropsychological outcome of children who had a heart operation in the new- born or infant age. Project 1: Common CHD: This patient group includes children with common CHD who required an operation in the new-born and infant period, i.e.: patients who had an arterial switch operation with trans- position of the great arteries (TGA), as a common operation in the new-born period; children who had an operation of a ventricular septal defect (VSD) as the most common CHD; and children with surgical repair of a tetralogy of Fallot (TOF) as a cyanotic CHD. Project 2: Resuscitation and mechanical circulation support: Included is patients who had a resuscitation (longer >five minutes) and an implantation of an extracorporeal membrane oxygenation and ventricular assist device. The central measurement instrument is the Bayley Scales of Infant Development, which is a pediatric development test and consists of a series of developmental play tasks used to derive a developmental quotient. The patients will be tested at the age of one, two and three years. In summary, we would like to evaluate the neuropsychological development of children after surgical repair of a TOF, VSD or TGA, compare it to the normal development of children, and determine if there are differences between these patient groups. Finally, we will study the neuropsychological development of children after resuscitation and mechanical circulation support.
Dr. med. Dominique Piber
Charité – Universitätsmedizin Berlin, Department of Psychiatry and Neurosciences
Email: dominique.piber@charite.de
Fields of Research
- Psychoneuroimmunology
- Depression
- Metabolic disorders
Project Title
Exploring Inflammatory Pathways Linking Depression and Comorbid Obesity
Project Description
Major depressive disorder (MDD) is associated with alterations in numerous biological systems, including a dysfunction of the immune system. While the cellular source of inflammation in MDD is still poorly understood, accumulating data point towards an increased activation of monocyte cell populations in depressed patients. Indeed, several studies, including prior work of our group, demonstrated that patients with MDD show an expansion of non-classical monocytes (also commonly referred to as »proinflammatory monocyte phenotype«). In addition, MDD frequently co-occurs with other inflammation-related conditions, such as metabolic syndrome and obesity. Interestingly, obese patients are reported to show a proinflammatory monocyte phenotype, which parallels previous findings in MDD. However, prior research has evaluated the proinflammatory monocyte phenotype in MDD and obesity only in separate studies. Furthermore, given that MDD and obesity have both been linked to inflammation, patients with comorbid MDD and obesity
might be especially suitable candidates for clinical trials of anti-inflammatory agents. Thus, the present BIH-project comprises two studies: a cross-sectional and a longitudinal study. The cross-sectional study examines putative differences in the proinflammatory monocyte phenotype and molecular signature across patients with MDD, obesity, comorbid MDD and obesity, and healthy controls. The longitudinal study, embedded in an ongoing RCT, examines whether add-on simvastatin (a lipid-lowering agent with pleiotropic effects including anti-inflammatory properties) to standard antidepressant treatment alters the proinflammatory monocyte phenotype and molecular signature in patients with MDD and comorbid obesity. The present BIH-project aims to provide new insights in the shared cellular and molecular inflammatory pathways of MDD and comorbid obesity, which could translate to new antidepressant therapies for comorbid patients.
Dr. med. Laura Pletsch-Borba
Charité – Universitätsmedizin Berlin, Department of Endocrinology and Metabolic Diseases
Email: laura.pletsch-borba@charite.de
Fields of Research
- healthy ageing
- Insulin sensitivity
Project Title
Prevention of age related diseases by a dietary intervention rich in polyunsaturated fatty acids and protein: A detailed analysis of a 36-month randomized intervention and further insights in underlying mechanisms
Project Description
The European population older than 65 years is expected to rise from 16% in 2010 to nearly 30% in 2060 and with it, an increase in cardiovascular diseases, type 2 diabetes and sarcopenia has been observed. The term “healthy aging” is becoming increasingly important in referring to a successful adaption to the changes caused by age-increase. The NutriAct is a randomized multicenter controlled trial, which investigates the effects of a high-PUFA-high-protein dietary pattern in healthy ageing. With this project, we target i) to acquire a deep understanding of the effect of an isoenergetic high-PUFA-high-protein diet in cardiometabolic diseases, physical function and health in elderly, ii) to investigate potential mechanistic pathways mediating those changes and iii) to study factors related to a higher modulation of the dietary pattern.
Dr. med. Julian Pohlan
Charité – Universitätsmedizin Berlin, Department of Radiology (including Pediatric Radiology)
Email: julian.pohlan@charite.de
Fields of Research
- Thermoablation
- CT-Thermography
- Dual-energy computed tomography
Project Title
CT-Thermography for Intraprocedural Ablation Zone Monitoring
Project Description
Using density data routinely acquired by computed tomography but neglected so far, it is now possible to provide an estimate on tissue temperature during thermoablation for operator feedback. Previous experiments in ex vivo porcine liver tissue indicated that heat ablation yields more accurate temperature estimates than cryoablation. Current challenges include the optimized coregistration of images in order to reduce breathing artifacts in the living animal. We are working on CT Thermography to improve the quality of thermoablation especially in renal cell carcinoma and thereby fight local recurrence.
Professional Experience
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Dr. med. Akira-Sebastian Poncette
Charité – Universitätsmedizin Berlin, Department of Anesthesiology and Intensive Care Medicine
Email: akira-sebastian.poncette@charite.de
Fields of Research
- Patient Monitoring
- Clinical Alarm Management
- Intensive Care Medicine
- Implementation Science
Project Title
INALO – Intelligent Alarm Optimizer for Intensive Care Units
Project Description
decades due to the monitoring of vital signs in intensive care units (ITS). However, between 72 and 99% of these alarms are described as false positives or »non-actionable «. They can trigger »alarm fatigue«, a desensitization of staff to critical alarms that can even lead to patient harm and even death. The goal of this project is to develop a user-centered platform that will enable research and implementation of alarm optimization approaches for patient monitoring in the ICU by means of patient-specifi c data and machine learning approaches. In doing so, the perspective is to achieve a reduction of unnecessary alarms. Digital documentation generates several gigabytes of health data every day. This data can already be used as a basis for artifi cial intelligence (AI) algorithms that support patient care in the ITS. The development of an alarm optimizer could promote a better understanding of the alarm situation, as well as reduce the workload of ICU staff and improve patient care by reducing unnecessary alarms.
PD Dr. med. Magdalena Sarah Prüß
Charité – Universitätsmedizin Berlin, Medical Department, Division of Gastroenterology, Infectiology and Rheumatology
Email: magdalena.pruess@charite.de
Fields of Research
- Gastroenterology
- Pain
- Immune System
Project Title
Functional Brain Changes and Pain Reduction in Patients with Inflammatory Bowel Disease
Project Description
Inflammatory bowel diseases (IBD) are associated with chronic pain in up to 38% of patients. Chronic pain conditions such as neuropathic pain have previously been shown to result in functional and structural changes in both the peripheral and the central nervous system (CNS). Those so-called maladaptive changes are described as the phenomena of hyperexcitability and hypersensitivity. Recently published work suggests an interaction be- tween the central and the enteric nervous system (ENS). Visceral pain in chronic pancreatitis has been associated with an inflammatory infiltration of pancreatic perineuria that includes macrophages, T-cells, and mast cells. We have previously shown that transcranial direct current stimulation (tDCS), a non-invasive method to transcranial modulate neuronal plasticity, is efficient to treat pain in IBD patients (Prüß/Volz et al., Pain 2016). Since the impact of tDCS on the CNS of IBD patients as well as putative effects on the mucosal immune system via activation of the ENS have not been studied yet, we aim to analyze the brain-gut axis by performing a prospective clinical phase-III-trial: tDCS will be applied to IBD patients to ameliorate IBD-associated pain. In parallel, the impact of tDCS on CNS structure and function (fMRI) as well as IBD disease activity and the dynamics of immune cell activity (mucosal and in peripheral blood samples) will be studied in patients before and after tDCS treatment. Finally, in search of the mechanistic link between stimulation of the CNS and mucosal inflammation, we will switch to a mouse model of colitis-associated chronic visceral pain. This will allow to address the interrelation of CNS, ENS, neurotransmitters production and mucosal inflammation and to study underlying mechanisms by assessing the role of a distinct set of neurotransmitters as well as the contribution of inflammatory cellular infiltrates. With this approach, we aim to decipher mechanistic insights of the gut-brain-axis and hence identify novel therapeutic targets.
Dr. med. Tobias Püngel
Charité – Universitätsmedizin Berlin, Department of Hepatology and Gastroenterology
Email: tobias.puengel@charite.de
Fields of Research
- Non-alcoholic steatohepatitis (NASH) & Fibrosis
- Immunology
- Metabolism
Project Title
In Depth Phenotyping and Functional Profiling of Macrophage Subsets in Chronic Liver Injury and Regression
Project Description
Non-alcoholic fatty liver disease (NAFLD) became the most common chronic liver disease worldwide and its prevalence is still increasing. NAFLD is closely associated with the metabolic syndrome and can progress to non-alcoholic steatohepatitis (NASH), which can further advance to fibrosis and ultimately liver cirrhosis. Strikingly, liver fibrosis is the main determinant of liver-related and overall mortality and in contrast to cirrhotic stages, liver fibrosis and NASH are considered as reversible. At present, therapeutic options beyond lifestyle modifications are limited and difficult to sustain – approved pharmacological therapies are still lacking. During disease progression of NASH and hepatic fibrosis multiple signalling pathways (e.g., disrupted metabolic and inflammatory responses) are dysregulated. Latest pathomechanistic insights prompted the experimental and clinical exploration of many new potential drug targets. In the current project we will further elucidate mechanistic insights of the cross-links between metabolism and inflammation in NASH and fibrosis progression. Going into detail, we will investigate effects of metabolism modifying interventions on macrophage functionality in experimental and human NASH employing up-to-date techniques (e.g., Single-cell RNA sequencing, 3D liver biochip system). Among potential inflammatory targets myeloid liver cells (Monocytes and Monocyte-derived Macrophages) emerged as key players orchestrating disease progression. Therefore, we will further elucidate effects of pharmacologically targeting macrophage recruitment on dysmetabolism in NASH and fibrosis. In a recent study we could demonstrate that targeting several PPAR isoforms in different cellular components of the liver (e.g. hepatocytes – PPARα, macrophages – PPARδ, stellate cells – PPARγ) dramatically improved the NASH phenotype over single PPAR isoform targeting in experimental mouse models (Lefere S*, Puengel T* et al, JHEP 2020). Based on these findings and as currently still ongoing clinical trials indicate that single drug treatments demonstrate lacking efficacy in reaching relevant endpoints such as fibrosis regression, we will additionally explore the prospects of rationally designed combination therapies in NASH and fibrosis.
Dr. med. Judith Rademacher
Charité – Universitätsmedizin Berlin, Medical Department, Division of Gastroenterology, Infectiology and Rheumatology
Email: judith.rademacher@charite.de
Fields of Research
- Acute Anterior Uveitis
- Axial Spondyloarthritis
- Biomarkers
Project Title
Early Recognition of Axial Spondyloarthritis in Patients with Acute Anterior Uveitis: Establishing and Validation of an Early Referral Tool
Project Description
The diagnostic delay in axial spondyloarthritis (axSpA) still remains high at around nine years. Early diagnosis in axSpA is especially relevant as short disease duration is one of the best predictors of good clinical response to therapeutic treatment and the halt of radiographic progression. The major barrier for early diagnosis in axSpA is a late referral of patients to rheumatologists. Acute anterior uveitis is a common extra-articular axSpA manifestation as more than 20% of patients with axSpA develop in the course of their disease and vice versa, 20- 40% of the patients with acute anterior uveitis suffer from axSpA. In many of them, the disease is not recognized when the first uveitis episode occurs. Recently, the Dublin Uveitis Evaluation Tool (DUET) for detection of undiagnosed spondyloarthritis in patients presenting with acute anterior uveitis was proposed by Haroon et al. (Ann Rheum Dis 2015) consisting of three steps (ques- tion about back pain, HLA-B27 test and psoriasis evaluation). With this study, we are analyzing whether an early recognition of patients with high probability of axSpA among patients with acute anterior uveitis is possible if an adaption of the Assessment of SpondyloArthritis International Society (ASAS) referral tool (Poddubnyy et al, Ann Rheum Dis 2015) is applied on the level of ophthalmologists. Following the ASAS referral tool, all patients with acute anterior uveitis and chronic back pain (> 3 months) with a beginning before 45 years should be referred to a rheumatologist. Thus, the ASAS tool might be more applicable for ophthalmologists who do not have the possibility of HLA-B27 testing or psoriasis evaluation. The performance of this ASAS referral tool will then be compared to the DUET. Moreover, we have extended the referral study to an inception cohort and will thus monitor patients with the history of acute anterior uveitis with and without axSpA over a period of up to ten years. We hope to gain a deeper insight into the disease’s course with this inception cohort.
Dr. med. Rolf Otto Reiter
Charité – Universitätsmedizin Berlin, Department of Radiology (including Pediatric Radiology)
Email: rolf.reiter@charite.de
Fields of Research
- Quantitative MRI
- MR Elastography
- Deep Learning
- Inflammation
Project Title
Quantitative Spatially-Resolved MRI Of Fibrosis and Inflammation in Chronic Liver and Bowel Disease
Project Description
Purpose: The aim is to determine fibrosis and inflammation in chronic liver and intestinal diseases using quantitative MRI (qMRI) and artificial intelligence. Background: Determination of disease activity of fibrosis (scar tissue) and inflammation is often crucial for therapy, but so far can only be determined with invasive procedures, such as biopsies or endoscopies. This is particularly true for
cholestatic liver disease (e.g., primary sclerosing cholangitis), fatty liver disease, and inflammatory bowel disease (Crohn's disease and ulcerative colitis). These diseases share a common diagnostic gap: determining the spatial distribution -or heterogeneity- of fibrosis and inflammation. Methods: Spatially resolved qMRI can measure this heterogeneity using the following sequences: Tomoelastography (shear-wave speed in m/s), T1 and T2 mapping (relaxation times in ms), diffusion imaging (ADC in mm2/s), fat quantification (in %). Image acquisition and image processing of multiple quantitative biomarkers simultaneously creates a system-independent database and provides the basis to train neural networks. This enables identification of the best parameters for classification of fibrosis and inflammation in liver and intestine. Automated diagnosis of the quantitative image data is performed using a 3D Multi-Channel Convolutional Neural Network. In this process, the different biomarkers can be tested separately and in all possible combinations. Clinical benefit: The number of
invasive procedures, such as biopsies, endoscopies, and surgeries, could be reduced. In addition, specific biomarkers could be established for stratification of clinical trials and development of new therapies.
Dr. med. Susanne Rittig
Charité – Universitätsmedizin Berlin, Department of Hematology, Oncology and Cancer Immunology
Email: susanne-malaika.rittig@charite.de
Fields of Research
- Immunotherapy
- Multiple Myeloma
- Dendritic Cell
Project Title
Augmenting Dendritic Cell Function for Rational Immunotherapies in Multiple Myeloma
Project Description
Multiple Myeloma (MM) is a heterogeneous hematologic malignancy with courses varying from asymptomatic stages to aggressive disease. Despite a plethora of approved therapies the disease largely remains incurable. Hence, novel anti-cancer therapeutic approaches combining efficacy, tolerability and minimal treatment burden are much-needed. Cancer vaccines have shown to be mainly well-tolerated and can promote long-term specific anti-tumor immune responses. Dendritic cells (DCs) as the most potent antigen-presenting cells are vital players in inducing, maintaining and regulating these immune responses and therefore represent a crucial component of vaccination. Considerable objective responses have been achieved with DC-based vaccines. However, this approach alone has not yet met expectations concerning the clinical outcome. Considering this low clinical efficacy, approaches combining therapeutic cancer vaccine strategies with approved agents are being designed. This provides the opportunity to introduce cancer vaccines into treatment at an early point of disease before onset of severe immune exhaustion. However, a critical challenge in using therapeutic agents to promote cancer immunotherapy is that they potentially also influence immune cells in the tumor microenvironment, possibly further impairing their ability to mount immune responses to dying tumor cells. Our group and others have previously demonstrated altered DC phenotype and impaired function by exposure to various therapeutic agents and we focus on elucidating the influence of further therapeutic drugs in order to identify optimal partners for DC-based immunotherapies. Another scientific interest is the role of checkpoint molecules in MM. In contrast to a variety of other cancers, immune checkpoint blockade, e. g. using blocking antibodies to the Programmed cell death protein 1 or its ligand to date has failed to achieve clinical efficacy in MM. Here too, an exhausted immune system may be the reason for missing response. Even though DCs are dominant partners of T cells, the role of DCs in this setting is not well-characterized. Furthermore, other immune checkpoints may be of relevance. One molecule we seek to further analyse in DCs is Osteoactivin, which was recently shown to be an immune checkpoint that impairs T-cell activation. We plan to further elucidate the role of checkpoint molecules in DCs for a possible targeted manipulation of T cell responses in the context of DC-based immunotherapies.
PD Dr. med. Julian Rogasch
Charité – Universitätsmedizin Berlin, Department of Nuclear Medicine
Email: julian.rogasch@charite.de
Fields of Research
- Quantitative Image Parameters
- Non-Small Cell Lung Cancer
- Machine Learning
- Image Biomarkers
Project Title
Machine Learning and Quantitative FDG PET-CT Image Parameters for Diagnostics and Prognosis in Patients with Lung Cancer
Project Description
This project investigates the additional value of machine learning (ML) and quantitative image parameters from FDG-PET/CT in patients with non-small cell lung cancer (NSCLC). In the current clinical application of FDG-PET/ CT, it is usually assessed as an isolated diagnostic tool, and reporting is mostly confined to visual reading. Consequently, the reliability and reproducibility of FDG-PET/ CT reports is variable, which currently entails frequent confirmatory invasive diagnostic procedures. Therefore, substantial advances in the clinical impact of FDG-PET/ CT in improving patient-relevant outcomes may require new paradigms. In this project, ML is used both to derive the image biomarkers and to integrate image data with clinical information, pathology reports and lab results (so-called integrated diagnostics). Different ML methods are investigated, including decision trees as well as deep learning (artificial neural networks). The first application of this methodology is in pretherapeutic thoracic lymph node staging in patients with NSCLC. Retrospective and prospective clinical data are used to develop and validate ML models that provide a differentiated and individualized estimate of the positive and negative predictive value of FDG PET/CT. The goal is to equip clinicians with a decision support system that is ready for clinical use and that allows individualized assessment of the reliability of FDG-PET/CT. This would help physicians to spare more patients additional (confirmatory) invasive staging. The second application that is investigated is the use of ML and quantitative image parameters to predict the patient’s survival after curatively intended treatment. Presently, the treatment decision is mainly determined by the clinical tumor stage although this is not sufficiently differentiated to allow individualized prediction of the patient’s prognosis and the optimal treatment. The current project investigates the additional value of textural features from FDG-PET and CT data to predict the progression-free survival and overall survival in patients with stage I-III NSCLC. These textural features include conventional, mathematically defined features (»radiomics«) as well as classificators derived with deep learning.
Dr. med. Tizian Rosenstock
Charité – Universitätsmedizin Berlin, Department of Neurosurgery
Email: tizian.rosenstock@charite.de
Fields of Research
- Deep neural networks
- Navigated transcranial magnetic stimuation
- Brain tumor surgery
Project Title
Development of Neural Networks for Brain Tumor Patient Imaging Analysis
Project Description
The gold standard for treatment of intrinsic brain tumors is a complete resection since the extent of resection (EOR) is positively correlated with (progression free) survival. However, the goal of complete tumor removal should always be balanced with preservation of function, because eloquent brain tumors imply the risk of a new functional deficits which not only lead to reduced quality of life, but also to reduced survival. We recently validated our risk stratification model based on regression tree analysis that enables to estimate the risk of postoperative motor deficit based on navigated transcranial magnetic stimulation [nTMS] and diffusion tensor imaging (DTI) data. A tumorous motor cortex infiltration and a distance ≤8mm to the corticospinal tract were risk factors for the development of a new postoperative motor deficit. In these cases, the risk was even higher if we could demonstrate impaired cortical excitability, which is determined by the motor resting threshold. The aim of this project is to combine different modalities such as structural MRI scans (with diffusion tensor imaging), nTMS data and patient characteristics using deep neural networks to further increase the accuracy of motor outcome prediction and identify new correlations where appropriate. In our initial analysis, we built on deep neural networks to predict the patients’ postoperative motor status based solely on their preoperative T1 with contrast agent scans. To improve our model performance, we decided to completely revise and adapt the preprocessing of the data and to integrate different modalities in our model as well. After training the model, its performance is further improved by expert validation (supervised learning) and by integrating external data In collaboration with other neurosurgical centers. We plan to develop a freely available web-based decision support tool that can be accessed by any neurosurgeon. In a web-based template, the treating neurosurgeon can enter all relevant patient characteristics and upload the available MRI and nTMS data. The probability of perioperative risk for a new motor deficit is provided, as well as an estimate of the patient's EOR, tumor histology, and survival rate. Relevant risk factors such as tumor motor cortex infiltration or corticospinal tract involvement are reported in a standardized manner.
Dr. med. Lisa-Maria Rosenthal
German Heart Center Berlin, Congenital Heart Defects - Pediatric Cardiology
Email: rosenthal@dhzb.de
Fields of Research
- Congenital Heart Disease
- Single Ventricle
- Remote Patient Monitoring
Project Title
Digital Care Hub for In-Home Surveillance of Infants with Single Ventricle Heart Disease
Project Description
Children born with single-ventricle heart defects (SVHD) have been experiencing substantial improvements from compassionate care to long-term survival due to the development of an innovative three-stage surgical palliation. After the first surgery, children are particularly at risk for life-threatening events with high mortality rates up to 20%. This has led to the implementation of in-home or in-hospital surveillance strategies. Long hospital stays and frequent visits at the outpatient department are necessary to date resulting in a poor quality of life for the children and their families. The digital care hub for in-home surveillance of infants with SVHD is a prospective longitudinal cohort study to investigate an application-based remote patient monitoring. With the application “Evie” caregivers will be asked to conduct and record daily measurements of vital parameters and fluid intake of their SVHD children. Data will be transferred to the health care team. Weekly video consultations will be performed and caregivers will periodically report the health-related quality of life of their children with ePROMs (electronic patient-reported outcome measurements). The aim of the study is to avoid life-threatening events, to optimize heart failure therapy and somatic growth of the children while reducing the number of hospital admissions and appointments to improve their health-related quality of life. Furthermore the adoption of technology and the impact on therapy adherence by caregivers will be investigated.
Dr. med. Rosa Rößling
Charité – Universitätsmedizin Berlin, Department of Neurology and Experimental Neurology
Email: rosa.roessling@charite.de
Fields of Research
- Autoimmune encephalitis
- Neuronal surface antibodies
- CRISPR Cas technology
Project Title
Identification of New Antibody Targets in Autoimmune Encephalitis
Project Description
Autoimmune encephalitis caused by antibodies targeting neuronal surface antigens is an only recently explored neurological disease that leads to psychiatric and mnestic deficits as well as epileptic seizures and focal neurological signs. New disease-causing antibodies are frequently being detected. Yet in clinical routine, we see many patients with unclear antibody findings, with the pathogenicity being unknown. Precise description of the antigen could not only work as proof of pathogenicity but also justify advanced immunotherapy in patients. It thus represents an immediate medical need. Today detection of an autoantibody using immunohistochemical methods is relatively easy and well established. The exact identification, however, of the antigen targeted by the antibody is still challenging. Even advanced methods using mass spectrometry or phage display fail to identify the complex membrane-expressed native receptor proteins. The proposed project therefore aims at identifying the surface receptors targeted by anti-neuronal autoantibodies by applying a new genome-wide screening method using the CRISPR/Cas9 activation technology. The CRISPR/Cas system is originally known from bacteria where exposition to viral DNA leads to integration in the bacterial genome by inducing double strand-breaks and thus providing a vaccination against future viral invasion. In our project we use a mutated, catalytically inactive (dead) nuclease dCas9 which is still able to bind DNA with high precision. If the dCas9 is led to the promoter region of its target gene by a so-called single guide RNA (sgRNA), it can act as a transcriptional regulator, amplify gene expression, and thereby promote expression of receptor subunits or whole receptors to the cell surface. The use of a genome-wide library of guide RNAs, containing all possible antibody targets, allows for inducing the overproduction of each single antigen in the respective cells. If a patient-derived antibody now binds to one of these cells, we can stain this antibody-labelled cell, sort it by flow cytometry, and select the positive cells. Cells can then be analysed by next-generation sequencing. Identification of the antigens would allow to better judge the autoimmune findings, guide therapeutic options, and facilitate development of target-selective immunotherapy in the future.
Dr. med. Marie Schafstedde
Charité – Universitätsmedizin Berlin, Institute of Computer-assisted Cardiovascular Medicine and German Heart Center Berlin, Congenital Heart Defects - Pediatric Cardiology
Email: schafstedde@dhzb.de
Fields of Research
- Image-Based Numerical Modelling
- Machine Learning
- Digital Health
Project Title
Precision therapy planning in heart diseases - A digital solution combining AI, computational modelling & synthetic data
Project Description
Valvular heart diseases are one of the most common causes of heart failure that can affect both, children and adults. Accurate treatment planning is therefore crucial but can be very challenging especially in complex valve defects such as combined aortic stenosis and mitral valve regurgitation. To date, clinical guidelines are based on rather indirect parameters such as valve orifice area, heart size or pressure gradients to determine if and when an intervention is recommended. However, they do not provide any support as to which procedure will have the best functional outcome in an individual patient. Especially within the interdisciplinary decision process of the “Heart Team”, digital support systems could help the physician not only with the optimal timing but also with deciding which type of intervention provides the best results (e.g., surgical vs. interventional valve replacement; one vs. double valve intervention). Due to the high prevalence of valvular heart diseases, such solutions would have a very high socio-economic impact.

The aim of this project is hence to develop a digital treatment planning solution that combines Artificial Intelligence (AI) and physiology-based models, allowing physicians to simulate treatment strategies and their hemodynamic outcomes for heart valve diseases interactively and in real-time.

To achieve this task, different digital methodological approaches will be applied:
Firstly, a statistical shape model of the aortic and mitral valve as well as the left ventricle is generated based on patient-specific reconstructions of those anatomical structures. This allows the generation of synthetic anatomies, increasing the amount of existing clinical data and thereby the training data set for the AI-algorithms trained subsequently.
Secondly, for each clinical and synthetic anatomy, hemodynamic information will be provided using computational fluid dynamics, a method allowing simulation of spatially and temporally resolved blood flow in complex, anatomical structures. Thus, the complete hemodynamic information as well as derived parameters relevant for clinical use are calculated for each case.
Thirdly, AI-based methods are then trained on this data to learn predicting hemodynamic parameters based on the anatomical information only.
The results of the interactive real-time therapy planning solution will finally be validated against existing clinical data.
Prof. Dr. Jan Friedrich Scheitz
Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology
Email: jan.scheitz@charite.de
Fields of Research
- Cardiac imaging after stroke
- Brain-heart interaction
- Post-stroke cardiovascular complications
Project Title
Brain-heart interaction
Project Description
Jan F. Scheitz is consultant stroke neurologist and Professor of Clinical Stroke Research at the Department of Neurology Charité in Berlin, Germany and at the Center for Stroke Research Berlin (CSB).
Dr. Scheitz is head of the research group “Integrative Cardio-Neurology”. Together with his group, his major research interests include all aspects of Heart & Brain interaction, post-stroke (cardiac) complications, mechanisms and prognostic impact of cardiac troponin elevation after stroke, and use of cardiovascular MRI in acute stroke.
His major motivation is to improve clinical awareness of post-stroke cardiac complications, and to promote interactive collaborations between stroke neurologists and cardiologists.
He is Fellow of the European Stroke Organisation (FESO) and founding member of the „Heart&Brain Task Force“ of the World Stroke Organisation (WSO).
Dr. med. Frieder Schlunk
Dr. med. Eva Vanessa Schrezenmeier
Charité – Universitätsmedizin Berlin, Medical Department, Division of Nephrology and Internal Intensive Care Medicine
Email: eva‐vanessa.schrezenmeier@charite.de
Fields of Research
- Acute Kidney Injury
Project Title
Identification of Biomarkers for Acute Kidney Injury
Project Description
Acute kidney injury is a common and potentially life-threatening condition. At the moment the diagnosis of AKI is made by a rise in serum creatinine. The serum creatinine level acts as a measure of the glomerular filtration rate. When the glomerular filtration rate decreases in case of AKI it can take up to 48 hours before an increase in se- rum creatinine is detectable. This leads to a delayed diagnosis of kidney injury. Some new biomarkers e.g. neutrophil gelatinase-associated lipocalin (NGAL) can detect kidney injury already two hours after the causing event. However, these new markers, as well as serum creatinine, stay elevated for several days after the causing event. The expression profiles of these new biomarkers allow the detection of AKI in an early phase but not the assignment to a time phase of AKI. We were able to show in a mouse model of ischemia-reperfusion that cation trans- port regulator homolog 1 (Chac1) is transcriptionally induced in an early phase of AKI. The expression is very short-range and already 48h after the causing event the mRNA levels of Chac1 has normalized to baseline. This is in contrast to the intrarenal mRNA level of NGAL and serum creatinine, which are elevated in all phases. With- in the junior CSP, the results on Chac1 could be validated in a preliminary study of human AKI. ELISA development for this new biomarker for larger proof-of-concept studies is on its way.
Dr. med. Jens Florian Schrezenmeier
Charité – Universitätsmedizin Berlin, Department of Hematology, Oncology and Cancer Immunology
Email: jens-florian.schrezenmeier@charite.de
Fields of Research
- Long-read sequencing
- Genomics
- Hematologic Malignancies
- Molecular Diagnostics
Project Title
Improved Molecular AML Diagnostics-Prerequisite for Individualized Patient Management
Project Description
Genetics and cytogenetics play a pivotal role in diagnosis and treatment of acute myeloid leukemia (AML) but also other malignancies such as Lung Cancer and Multiple Myeloma. Improvements in AML genetic diagnostics are a prerequisite for individualized patient management. Yet, current second generation sequencing methods are hard to implement into daily clinical routine with regard to the application of rapid cytogenetics and methylation profiling. To address these clinical needs in AML and
other malignancies we will use third generation long-read (Nanopore) sequencing that allows to directly read information from the nucleic acid strand enabling rapid high-resolution karyotyping and access to DNA and RNA modification information that was out-of-reach in molecular diagnostics. Access to this new dimension of molecular information will lead to a better understanding of disease biology and improve treatment approaches.
Dr. rer. medic. Maria Sekutowicz, M.Sc.
Charité – Universitätsmedizin Berlin, Department of Anesthesiology and Intensive Care Medicine
Email: maria.sekutowicz@charite.de
Fields of Research
- Postoperative Delirium
- Multivariate Prediction
Project Title
Neuropsychiatric biomarkers for the prediction of postoperative delirium
Project Description
By using machine learning techniques complex and multidimensional routine data can be utilized for the individual prediction of postoperative delirium (POD). Delirium incidence after surgery ranges from 5-54% for different patient cohorts and is associated with high complication rates, prolonged hospitalization and increased mortality. In the literature a variety of serological, molecular and neuroimaging factors have been described to be relevant for the pathogenesis of POD. On the neurobiological level functional connectivity as well as volumetric measures have been associated with POD. However, as the neurocognitive mechanisms behind POD have not been fully uncovered prediction of POD on an individual level remains insufficient. In my project I will use multivariate analyses and include magnetic resonance images to establish a machine learning algorithm that will be validated in big routine data to predict POD. A similar approach has already been successful in past, where a multivoxel classification algorithm was used to predict relapse in alcohol dependent patients and future drinking in an independent cohort of young adults (Sekutowicz et al., 2019). Besides neurocognitive symptoms, also affective and psychotic symptoms occur frequently in POD patients including forms of perceptional disturbances, hallucinations and delusional thinking. Clinical as well as subclinical depression has already been identified as a risk factor for POD. Therefore, it may be hypothesized that clinical but also subclinical symptoms along a continuum between normal and delusional thinking account as predisposing factors for the development of POD. To evaluate this hypothesis patients with POD will be analyzed according to their psychiatric comorbidities in routine data as well as according to their psychosis proneness. Taken together, this project aims at a multivariate prediction of POD to pave the way for a clinically applicable practice and get further insight into predisposing factors for POD.
Dr. med. Elise Siegert
Charité – Universitätsmedizin Berlin, Department of Rheumatology and Clinical Immunology
Email: elise.siegert@charite.de
Fields of Research
- Immunology
- B cells
- COVID
Project Title
Neuromuscular Involvement in Systemic Sclerosis
Project Description
The aim of my project is to assess the prevalence and nature of neuromuscular involvement in Systemic Sclerosis (SSc). SSc is a rare connective tissue disease characterized by the pathophysiological triad of microvascular dysfunction, tissue fibrosis and autoimmune inflammation. Specifically, we will screen patients for symptoms of small fiber neuropathy (SFN) and confirm the diagnosis by skin biopsy. Recent studies show that approximately 45% of all patients suffer from neuropathic pain. However, there is no study systematically evaluating potential causes of neuropathic pain in SSc. Even though SFN is a well-recognized complication of other connective tissue diseases such as Systemic Lupus Erythematosus, it has not been assessed as a cause for neuropathic pain in SSc, yet. Our hypothesis is that SFN is a common complication of SSc. In a second project we will perform a retrospective analysis of SSc muscle biopsies according to current neuropathological standards. We will try to identify a morphological pattern that is specific to SSc. We reckon that the origin of neuromuscular involvement in SSc is not only destructive fibrosis and obliterative vasculopathy, but that the interplay between immune cells and nerve cells is responsible for peripheral tissue damage.
Dr. med. Laura Katharina Sievers
Charité – Universitätsmedizin Berlin , Medical Department, Division of Nephrology and Internal Intensive Care Medicine
Email: laura‐katharina.sievers@charite. de
Fields of Research
- Hypertensive End‐Organ Damage
- CD4+ Lymphocytes
- Hippo Signaling
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. Farzan Solimani
Email: farzan.solimani@charite.de
Fields of Research
- Dermatology and Immunology
Project Title
Functional characteristics of T (follicular) regulatory cells in pemphigus
Project Description
Pemphigus, a severe blistering disorder of skin and mucosa characterized by autoantibodies against desmosomal proteins of the skin, is a model disease to study autoimmunity in humans. A harmed immunosuppressive capacity of T regulatory cells (Treg) is one of the critical checkpoints leading to autoimmunity, since their deficiency or impairment facilitates the disruption of immune homeostasis. Treg cells constitute ~5% of circulating CD4+ T cells, and are characterized by the lineage marker forkhead box protein P3 (FoxP3). Treg cells can be defined through detection of FoxP3 and by their expression of CD25 and CD127 (CD4+CD25+CD127low). Accordingly, similarly to several other autoimmune disorders, there is a wide literature demonstrating that the function of Treg cells is impaired in pemphigus. T Recent advances depict a more complicated mosaic. For instance, it has been shown that some Treg cells - beside their classical production of the anti-inflammatory interleukin (IL)-10 - may produce IL-17 or Interferon (IFN)-ɣ, thus indicating that this cell group is more heterogeneous than previously described and could therefore differently be implicated to dampen inflammation. Recently, a follicular counterpart of Treg cells has been described, namely T follicular regulatory (Tfreg). These cells can migrate in to the germinal centers and modulate the immune answer due to the expression of the chemokine receptor CXCR5. The role of this cell population is controversial. While some studies described these cells as anti-inflammatory, there is also evidence that under some circumstances Tfreg can support inflammation and antibody formation in germinal centers. In the setting of influenza virus infection, Tfreg are necessary for the generation of virus specific long-lived plasma cells and for antibody production. Yet, a recent study rather describe an anti-inflammatory role for Tfreg cells, which can dampen B cell activity through release of neuritin. In Pemphigus, several studies tried to analyze the role of Treg cells, whereas any group investigated the role of Tfreg cells. Some studies detected the presence of lower levels of Treg cells in pemphigus patients compared to healthy controls, and the induction of Treg cells has been associated to decreased pathogenicity in a HLA-transgenic mouse model of Pemphigus.
In pemphigus, neither the heterogeneity of the Treg/Tfreg cells nor their different capacity to modulate inflammation have been analyzed. This project aims to elucidate the heterogeneity of the Treg/Tfreg subset in pemphigus. The definition of specific subset, which may carry stronger immunosuppressive capacity than others, may help to detect new therapeutic targets in this strongly debilitating autoimmune disorder.
Dr. med. Lara Mirja Steinbrenner
Charité – Universitätsmedizin Berlin, Department of Neurology and Experimental Neurology
Email: mirja.steinbrenner@charite.de
Fields of Research
- Epilepsy
- MRI
- EEG
- Epilepsy Surgery
Project Title
Using Computational MRI to Automatically Detect Epileptogenic Lesions in Patients Eligible for Epilepsy Surgery
Project Description
Epilepsy affects about 70 million people worldwide; it is one of the most common neurological disorders in children and adults. Up to one third of patients are drug-resistant, with poorly controlled seizures despite adequate medication. Epilepsy surgery is the most successful treatment option to achieve seizure freedom for patients with focal drug-resistant epilepsy, which on average is achieved in 65% of patients. The absence of an epileptogenic lesion on MRI has been shown to decrease the probability of seizure freedom by more than 20%. The detection of an epileptogenic lesion on MRI in so far assumed non-lesional pre-surgical candidates remains an important challenge to improve surgical targeting and secondarily postsurgical outcome. In this retrospective study, we assess a new approach to detect individualized lesions in patients with epilepsy in a large cohort, two-center study by applying an outlier lesion detection machine-learning algorithm. Pre- and if available postoperative MRI scans (T1-weighted (T1 MPR) and T2-weighted FLAIR) of all consecutive patients having received a recommendation to undergo epilepsy surgery, between 2015 and 2020 at the Epilepsy centers in Berlin and Bochum, will be analyzed. Clinical variables, including the clinical and neurophysiological focus hypothesis consensus from the multidisciplinary meetings (MDM), will be collected for each patient. Additionally, we are comparing this new approach to previously published methods by applying them to the same data set. The primary outcome measure is the outlier lesion concordance with the epileptogenic focus defined by MDM consensus. Concordance is defined by localization in the same gyrus or lobe (depending on specificity of presurgical lesion-hypothesis). The secondary outcome measure is the overlap between the outlier lesion and surgical resection site. In the long run, we hope, by applying the outlier lesion detection method successfully, to enable more surgeries in non-lesional cases and potentially cut down the use of invasive diagnostics such as intracranial EEG.
MD/PhD Leon Amadeus Steiner
Charité – Universitätsmedizin Berlin, Department of Neurology and Experimental Neurology
Email: leon-amadeus.steiner@charite.de
Fields of Research
- Deep Brain Stimulation
- Synaptic Mechanisms
- Human Single Cell Research
Project Title
Synaptic Mechanisms to Retune Inhibitory Control of the Subthalamic Nucleus in Patients with Parkinson’s Disease
Project Description
Deep brain stimulation (DBS) of the Subthalamic Nucleus (STN) is an effective treatment for Parkinson’s Disease symptoms. However, DBS only provides transient relief of symptoms, which rapidly return when stimulation is discontinued. To advance DBS therapy, a more thorough understanding of fundamental mechanisms is needed. Evidence from rodent studies has shown the potential of microcircuit interventions to induce long-lasting recovery of movement. Specifically, selective stimulation of inhibitory projections to the STN have been implicated in these effects. In humans, there is exciting new evidence that deep brain stimulation may serve to retune inhibitory synaptic control of basal ganglia structures. At present, however, inhibitory synaptic plasticity in basal ganglia structures has exclusively been studied in STN output structures in humans. In the rat, we have previously shown that the input of inhibitory projections is sustained at high stimulation frequencies in contrast to rapidly depressed excitatory input. Capitalizing on the unique opportunities of intraoperative microelectrode and human single-neuron recordings, this study aims to elucidate effects of the activation of inhibitory projections to STN by DBS in humans. Understanding the underlying physiological mechanisms of this aspect of DBS may be critical in optimizing DBS stimulation paradigms.
Dr. med. Helena Stengl
Teresa Straka
Charité-Universitätsmedizin Berlin, Klinik für Pädiatrie m.S. Onkologie und Hämatologie (CVK)
Email: teresa.straka@charite.de
Fields of Research
- pediatric oncology & hematology
- immunology
- oncology & hematology
Project Title
Development of AURKA inhibitor-resistant CAR T cells for advanced neuroblastoma killing
Project Description
Neuroblastoma is the most common extracranial, solid tumor in children, accounting for 15% of all pediatric cancer deaths worldwide. In neuroblastoma, a MYCN amplification is usually associated with high-risk groups, where patients are still facing survival rates of less than 50%, therefore highlighting the need for the development of new targeted therapies. One therapy option could be a combinational treatment consisting of two parts: Chimeric antigen receptor (CAR) T cell therapy combined with the Aurora Kinase A inhibitor (AURKAi) LY3295668, which indirectly inhibits MYCN. By enhancing the recruitment of CAR T cells to the tumor site and by improving tumor cell killing altogether, this combinational approach might be a promising treatment to improve CAR T cell therapy against MYCN amplified neuroblastoma. However, it was demonstrated that the function of Aurora Kinase A is necessary for proper effector function of CAR T cells. Therefore, the aim of my project is to generate neuroblastomaspecific CAR T cells, expressing an Aurora Kinase A mutant variant, which confers resistance to AURKAi LY3295668 in order to efficiently combine AURKAi with CAR T cell therapy, without compromising the effector function of CAR T cells.
Rahel Maria Strobel
Charité – Universitätsmedizin Berlin, Department of General, Visceral and Vascular Surgery
Email: rahel.strobel@charite.de
Fields of Research
- Visceral surgery
- Oncology
- Patient-reported quality of life
Project Title
NOTE – Necessity of Protective Ileostomy in Rectal Resection?
Project Description
Low anterior rectal resection for rectal cancer goes along with the creation of a protective ileostomy in most of the cases. A protective ileostomy can cause an immense deterioration of the patients‘ quality of life. Furthermore, postoperative complications such as excoration of the peristomal skin, peristomal abscesses, prolapse of the ileostomy or renal failure because of high fl uid losses occur in nearly 15%. Ileostomy reversal requires surgery once again with inherent hospital stay, healthcare costs and possible complications. But the patient’s safety in rectal resection must be mentioned as well. There are data that a protective ileostomy can lower septic complications caused by insufficiency of the rectal anastomosis. To further evaluate the necessity of protective ileostomy in low anterior rectal resection we conduct the NOTE trial which is a multicentric, prospective, randomised-controlled trial comparing patients with and without protective ileostomy undergoing rectal resection because of rectal cancer. Primary hypothesis says that patients without protective ileostomy have a better quality of life one year after rectal resection than patients with protective ileostomy measured by the mean score of the category »physical function« of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). There will be 224 patients overall, 112 each group, when a dropout rate of 10% is assumed. After randomisation of 25 patients in each group a safety analysis regarding operative revision because of insufficiency of rectal anastomosis will be conducted. All, inclusion criteria, surgical technique and perioperative management will be standardized. Three year follow-up of the patients includes both clinical examination and questionnaires as well as oncological outcome.
Dr. med. Alexander Thieme, M.Sc.
Charité – Universitätsmedizin Berlin, Department of Radiation Oncology and Radiotherapy
Email: alexander-henry.thieme@charite.de
Fields of Research
- Digital Health
- App Development
Project Title
Electronic Patient-Reported Outcomes for Relapse Detection in Cancer Patients and Mitigation of the Novel Coronavirus Pandemic
Project Description
Electronic Patient-Reported Outcomes (ePROs) promote patient-centered care by collecting and incorporating patient-reported information into clinical settings. At the heart of this digital health project, an open-source ePRO application (app) was developed with the flexibility to be adapted to various clinical situations and a focus on ease-of-use for the patient. Two different use cases are evaluated for this app: 1.) relapse detection for cancer patients, 2.) risk evaluation of users potentially infected with the novel coronavirus (SARS-CoV-2). Regarding use case 1, standard of care for relapse detection in cancer patients usually involves follow-up visits in fixed intervals.
This leads to unnecessary prolongation of relapse detection which can have a deleterious effect on the oncological outcome. ePROs facilitate that patients enter symptoms directly into a database that can be evaluated in real-time. Especially, patients with locally advanced head and neck squamous cell carcinoma (HNSCC) may profit from earlier relapse detection which is seen in 15-50% of the cases. HNSCCs are known to proliferate rapidly and deferred treatment can result in stage progression. Recurrent stage is known to be the most important parameter regarding overall survival. A model is built based on ePROs to detect patterns with the goal of earlier relapse detection with a lower recurrent stage. Machine learning methods are used for model creation in collaboration with Stanford University. For use case 2, the app has been published under the name CovApp and could demonstrate the ability of fast deployment during the onset of the novel coronavirus pandemic and scalability to a larger number of users. CovApp provided individualized recommendations based on ePROs regarding laboratory testing, probability of severe covid-19, and guidance for several million users in Germany and internationally. At the hospital, increased efficiency could be achieved by reducing the time necessary for anamnesis by providing the function to scan ePROs directly from the patient’s smartphone via QR code. Hereby, it contributed to identify and interrupt infection chains, optimize health care resources and provide crucial information to the general population, especially to high-risk patients. Further development aims to evaluate the project's big data for local outbreak detection and case number prediction.
Dr. med. Loredana Vecchione
Charité – Universitätsmedizin Berlin, Department of Hematology, Oncology and Cancer Immunology
Email: loredana.vecchione@charite.de
Fields of Research
- Translational research
- Biomarker discovery in CRC
- Identification of new therapeutical options in CRC
Project Title
Studying the Concordance of Molecular Subtypes of Primary and Metastatic CRC in Patient Samples and Organoids
Project Description
Focus on my research is the better understanding of the CRC biology in order to identify new therapeutical options for the treatment of CRC. To this end, we use CRC organoid models and we compare in vitro data with in vivo data. We furthermore stratify our models, as well as patients samples in different molecular subtypes in order to define subgroups who may benefit from existing and new emerging treatments.
Dr. med. Jan Voss
Charité – Universitätsmedizin Berlin, Department of Oral and Maxillofacial Surgery
Email: jan.voss@charite.de
Fields of Research
- bone healing
- immune system
Project Title
Biomarker for Impaired Bone Healing of the Mandible
Project Description
This prospective research project is a hypothesis-testing blinded study design. The project objective is to prospectively validate CD8+ TEMRA cells as a biomarker for impaired fracture healing in (A) mandibular corpus fractures and (B) mandibular osteotomies in the setting of mandibular displacement surgery. The project hypothesis here is that CD8+TEMRA cell expression acts as a potential prognostic biomarker with high diagnostic precision in terms of differentiating between normal and impaired fracture healing.
Dr. med. Tu-Lan Vu-Han, PhD
Charité – Universitätsmedizin Berlin, Center for Musculoskeletal Surgery
Email: Tu-lan.vu-han@charite.de
Fields of Research
- Drug Targeting Epigenetic Regulators
- Early Onset and Neuromuscular Scoliosis
- 5q-Spinal Muscular Atrophy
Project Title
ML-based Prediction of Scoliosis in SMA in Response to Novel Therapies
Project Description
5q-spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by the biallelic loss of the SMN1 gene. The absence of SMN1 transcripts leads to an SMN protein deficiency that causes progressive degeneration of anterior motor neurons and muscular atrophy. Patients with severe forms of disease manifestation often lack sufficient copy numbers of the gene paralog SMN2, which also encodes for the full-length SMN protein, but is truncated and rendered functionless through an alternative splicing mechanism.

Groundbreaking research throughout the past three decades has provided us with insights into the molecular genetic basis of SMA. These insights have fueled drug development to treat the underlying cause of this devastating disease: In 2017, the first FDA-approved antisense-oligonucleotide, splice-modification therapy nusinersen Spinraza® became available, which promotes the full-length transcription of SMN from available SMN2 genes. In 2019 the first gene replacement therapy arrived, onasemnogen Zolgensma®, which utilizes the AAV9 platform for delivery of SMN1 cDNA. In 2020, the first oral splice modification therapy, risdiplam Evrysdi®, followed.

SMA therapies have shown promising outcomes in increasing survival and improving motor functions in SMA patients. Thus, in December 2020, the Gemeinsamer Bundesausschuss (G-BA) approved the implementation of SMA in extended newborn screening programs, which will take a Germany-wide effect in October 2021.

Researchers, as well as medical practitioners, expect the efficacy of these novel therapies to change the natural history of the patient phenotype. As a result, many disciplines will require updated treatment standards and strategies for SMA-associated sequelae, of which the SMA-associated scoliosis is an essential one.

The objective of this project is to use a Machine Learning approach to predict SMA-associated scoliosis development in response to novel SMA therapies. Our ultimate goal is to provide a helper tool that will help physicians and surgeons in their decision-making during treatment optimization for SMA patients.
Katharina Wansch
Charité-Universitätsmedizin Berlin, Medizinische Klinik m. S. Hämatologie, Onkologie und Tumorimmunologie (CCM)
Email: katharina.wansch@charite.de
Fields of Research
- Translational oncology
- Organoids
- Gastroenterology
Project Title
Mechanisms of acquired chemotherapy resistance in pancreatic ductal adenocarcinoma in organoid models
Project Description
Pancreatic cancer represents one of the deadliest types of cancers with an overall survival rate of 10%. Effective treatment options are limited since pancreatic cancer shows high levels of chemotherapy resistance. Furthermore, no clinically established biomarkers have been determined for predicting the individual chemotherapeutic response of patients. As surgery represents the only curative treatment option of pancreatic cancer, effective adjuvant chemotherapy remains crucial. The high chemoresistance and ineffective treatment options, however, lead to relapse rates of up to 80%.
In recent years, organoid technology has provided a promising platform for studying the tumor physiology of pancreatic cancer. These models can be established from tumor tissue and used for functional analyses, which allows individual prediction platforms to be developed. Up until today, however, organoid models have been used to evaluate drug responses at a single time point only. For a better understanding to be gained, this project aims at developing a dynamic predictive platform as well as understanding the dynamic changes in chemotherapeutic resistance.
In the first part of the project, 10 patient-derived organoid cultures from treatment-naïve patients will be established and characterized by histology, immunohistochemistry, genomic sequencing and treatment response. To induce chemoresistance, the cultures will be exposed to several cycles of chemotherapy using the same regimens as in the clinic. We will identify mechanisms of resistance on a functional level by analyzing the transcriptome and proteome of the organoids before, during and after the chemotherapy. Moreover, a comparison to the clinical data of the patients will be made.
Whether individual cell clones possess an intrinsically resistant or an acquired resistant phenotype when exposed to chemotherapy, is yet to be determined. To differentiate mechanisms of clonal selection, single-cell organoids will be developed. These organoids allow the identification of primary resistant clones within the heterogeneous treatment-naïve tumor cell population.
In conclusion, our research project aims at developing a dynamic predictive platform for chemotherapy resistance in pancreatic cancer. This way, mechanisms of resistance can be identified and personalized drugs identified. In the long term, high-throughput drug screening in dynamic predictive platforms may allow future advances in pancreatic cancer treatment.
Dr. med. Julian Weingärtner
Charité – Universitätsmedizin Berlin, Department of Radiation Oncology and Radiotherapy
Email: julian.weingaertner@charite.de
Fields of Research
- Oncology
- Machine Learning
- Artificial Intelligence
Project Title
Artificial intelligence in functional imaging for individualized treatment of HNSCC patients
Project Description
Head and neck squamous cell carcinoma (HNSCC) represent the sixth most common cancer worldwide. The two curative treatment modalities for patients with HNSCC - primary chemoradiation (CRT) or primary surgery (often combined with postoperative (C)RT) - are both associated with serious side effects. Therefore, further stratification, optimization and personalization of treatment is urgently needed. As novel quantitative image analyses are a promising tool for further risk stratification, we´re training a three-dimensional Convolutional Neural Network on 18F-Fluorodesoxyglucose (FDG) positron emission tomography (PET) imaging and clinical / histopathological data of a multicentric, retrospective cohort of 1200 patients treated with primary CRT and 800 patients treated with primary surgery at Charité and cooperation institutes in order to predict individual treatment-specific outcomes and identify patients with excellent outcome after primary CRT or primary surgery or unfavorable outcome by both. The trained algorithm of the artificial intelligence will be validated in a prospective trial to see if predicted loco-regional control and recommended treatment strategies are reliable. In total 250 curative HNSCC patients, treated with CRT or primary surgery, will be enrolled on this prospective validation trial with observational character, while biomarker, clinical and FDG-PET data are collected from these patients and follow-up visits concluded.
Dr. med. univ. MSc. Nikolaus Wenger, PhD
Charité – Universitätsmedizin Berlin, Department of Neurology with Experimental Neurology
Email: nikolaus.wenger@charite.de
Fields of Research
- Motor Recovery
- Neuroprosthetics
- Stroke Research
Project Title
Inducible Neuroplasticity after Stroke using Neurotransmitter Replacement Strategies
Project Description
Translating the behavioral output of the nervous system into movement involves interaction between the brain and the spinal cord. The brainstem provides an essential bridge between these two structures. However, the function of this intermediary system in motor recovery after stroke remains poorly understood. In fact, the brainstem is a major source of monoaminergic neurotransmitters that coordinate movement at the level of the spinal cord (Wenger et al. 2016) and mediate plasticity in the central nervous system (Ng et.al 2015). My hypothesis is that motor cortex stroke alters the activity of monoaminergic brainstem nuclei limiting functional recovery after stroke. Using neural tracing experiments and behavioral analysis, I aim to investigate the therapeutic effect of monoaminergic neurotransmitter replacement strategies to engage plasticity of neural networks related to motor production. The translational aim of this project is to investigate neuroanatomical rewiring processes that benefit the restoration of function after stroke.
Dr. med. Kun Zhang
Charité – Universitätsmedizin Berlin, Department of Cardiology
Email: kun.zhang@charite.de
Fields of Research
- Calcium Signaling in Heart Failure
- Excitation‐Secretion Coupling in Cardiomyocytes
Project Title
The Heart as an Endocrine Organ: Chromogranin B and the Inositol-1,4,5-Trisphosphate Receptor in Excitation-Secretion Coupling in Cardiomyocytes
Project Description
In endocrine cells, a crucial role of chromoganin B (CGB) and the inositol-1,4,5-trisphosphate receptor (IP3R) in exocytosis of vesicles and hormone secretion is known. The heart owns characteristics of an endocrine organ as well. We could show that CGB as a marker of secretory granules is also expressed in cardiomyocytes and demonstrated a pathophysiological pathway of the CGB and IP3R interaction in cardiac hypertrophy and heart failure. While excitation-secretion coupling is well described in other excitable cells such as neurons, this concept is novel and not yet studied in cardiomyocytes. Aim of this project is to examine the functional role of CGB and the IP3R in excitation-secretion coupling in cardiomyocytes and in murine models of heart failure with preserved ejection fraction (HFpEF). Final goal will be to establish a pathway that can serve as a new target in heart failure treatment.
Dr. med. Marco Zierhut
Charité – Universitätsmedizin Berlin, Department of Psychiatry and Neurosciences
Email: marco.zierhut@charite.de
Fields of Research
- Negative symptoms
- Psychosis
- Schizophrenia spectrum disorders
Project Title
Oxytocin-augmented group psychotherapy for patients with schizophrenia
Project Description
The effectiveness of current treatment options for sociocognitive deficits and negative symptoms (NS) in schizophrenia spectrum disorders (SSD) remains limited. The cause of NS is thought to be an interference between the mesocorticolimbic dopamine system for social reward expectancy and the network for socioemotional processes. Oxytocin (OXT) may enhance functional connectivity between these neuronal networks. Lower plasma OXT levels correlate negatively with NS severity and deficits in social cognition in SSD. It has been shown that intranasal OXT administration improves social cognition, including empathy, in healthy subjects but in SSD results are inconsistent. According to the social salience hypothesis, the effect of OXT varies depending on the social context and individual factors. Also, OXT-mediated effects on psychopathology, NS, and empathy may depend on genetic variants of OXT receptors (OXTR). In a pilot study, we demonstrated a reduction in NS by OXT administration in a positive social context in SSD. We also demonstrated that NS and other symptoms improved after mindfulness-based group psychotherapy (MBGT). The aim of this study in individuals with SSD is to examine the effect of combining OXT administration with MBGT on NS, empathy, affect, and stress. The main hypothesis to be tested is that the use of OXT compared to placebo prior to MBGT in patients with SSD will result in a greater reduction in NS. The research design is based on an experimental, triple-blind, randomized, placebo-controlled trial. The manualized MBGT sessions are led by two psychotherapists over four weeks. Four sessions take place once a week in a group of six patients. The effects of OXT peak after 30-80 minutes for optimal reinforcement of social behavior. Patients receive 24 I.U. of OXT or placebo intranasally 30 minutes prior to each therapy session. Plasma OXT levels will be determined by radioimmunoassay. To exclude gender bias, both women and men will join mixed-sex groups controlled for hormones. Change in NS as the primary endpoint will be measured with validated interviews (Positive and Negative Syndrome Scale, PANSS) and psychometric questionnaires (Self-Evaluation of Negative Symptoms, SNS). Variables, including plasma OXT levels, will be measured at baseline and post-intervention and the role of genetic variations of the OXTR genes for the NS will be looked at exploratively.

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Dr. med. Jan Rafael Dörr

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PD Dr. med Cornelius Engelmann

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

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Dr. med. Karl Herbert Hillebrandt

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