Research Report of the Medical Faculty Reference Period

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1 Research Report of the Medical Faculty 2013 Reference Period

2 Content General Aspects 3 Preclinical Institutions Institute of Anatomy and Cell Biology 11 Institute of Molecular Biology and Tumorbiology (IMT) 18 Institute of Physiological Chemistry 23 Institute of Physiology and Pathophysiology 24 Department of Medical Psychology 30 Institute of Medical Sociology and Social Medicine 32 Clinical-theoretical Institution Institute of General and Family Medicine, Prevention and Rehabilitations 33 Institute of Medical Biometry and Epidemiology 36 Institute of Pharmacology and Toxicology 38 Emil-von-Behring-Library, Department of the History of Medicine 41 Institute of Clinical Cytobiology and Cytopathology 42 Institute of Immunology 45 Institute of Medical Microbiology and Hospital Hygiene 47 Institute of Virology 49 Centre for Human Genetics 55 Institute of Pathology 57 Division of Neuropathology 59 Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics 61 UMGL-Chair in Molecular Pulmonology 65 Clinical Institutions Department of Anaesthesia and Intensive Care Therapy 68 Department of Diagnostic Radiology 71 Department of Nuclear Medicine 75 Department of Radiotherapy and Radiooncology 77 Department of Internal Medicine: Division of Gastroenterology, Endocrinology and Metabolism 80 Department of Internal Medicine: Division of Hematology, Oncology and Immunology 86 Department of Internal Medicine: Division of Cardiology 92 Department of Internal Medicine: Division of Nephrology 95 Department of Internal Medicine: Division of Pneumology 96 Department of Internal Medicine: Division of Psychosomatic Medicine and Psychotherapy 101 Department of Cardiovascular Surgery 104 Department of Neurosurgery 107 Department of Orthopaedics and Rheumatology 109 Department of Trauma, Hand- and Reconstructive Surgery 112 Department of Urology and Pediatric Urology Prostate Cancer Centre 114 Department of Visceral-, Thoracic and Vascular Surgery 116 Department of Obstetrics and Perinatal Medicine 119 Department of Gynaecology, Gynaecological Endocrinology and Oncology 121 Children s Hospital 124 Department of Otolaryngology, Head and Neck Surgery 126 Clinic for Phoniatrics and Paedaudiology 130 Department of Ophthalmology 132 Departement of Dermatology and Allergology 135 Department of Neurology 140 Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy 144 Department of Psychiatry and Psychotherapy 147 Department of Oral and Maxillofacial Surgery, Oral Surgery and Implantology 153 Department of Orthodontics 157 Departement of Periodontology 158 Department of Operative Density and Endodontics 160 Department of Pediatric and Community Density 162 Department of Prosthodontics and Craniomandibular Function 164 Coordination Centre for Clinical Trials 167

3 General Aspects List of Abbreviations/Glossary BMBF BMFZ CCC DFG FOR GRK IMT JIF KFO KKS Federal Ministry of Education and Research Bundesministerium für Bildung und Forschung Biomedical Research Centre Biomedizinisches Forschungszentrum Comprehensive Cancer Center German Research Foundation / Deutsche Forschungsgemeinschaft Research Unit / Forschergruppe Research Training Group / Graduiertenkolleg Institute for Molecular Biology and Tumor Research Journal Impact Factor Clinical Research Unit / Klinische Forschergruppe Coordination Centre for Clinical Studies LOEWE State Offensive for the Development of Scientific-Economic Excellence / Landes-Offensive zur Entwicklung Wissenschaftlich-ökonomischer Exzellenz LOF LOM SFB TR Performance-related allocation of research and office space Performance-related Funding / Leistungsorientierte Mittelvergabe Collaborative Research Centre / Sonderforschungsbereich Transregional Collaborate Research Centre / Transregio UKGM University Hospital Giessen and Marburg Universitätsklinikum Gießen und Marburg ZTI Centre for Tumor and Immunobiology/ Zentrum für Tumor- und Immunbiologie

4 General Aspects General Aspects Main Fields of Research According to the criteria of the German Research Council (DFG) at the School of Medicine of the Philipps University Marburg the following preferred research clusters are established: Cellular Compartimentation and Disease Relevance Clinical Immunology and Infection Biology Oncology and Tumor Biology Associated infrastructural components already existent are the Biomedical Research Centre (BMFZ), the Institute for Molecular Biology and Tumor Research (IMT), the Comprehensive Cancer Center Marburg (CCC), the Carreras Leukaemia Centre and the Allergy Centre Hesse. Research Cluster Cellular Compartmentation and its Relevance for Disease The location of intracellular compartments and smaller entities such as protein complexes, nucleic acids, metals and lipids within a cell is prerequisite for the complexity and regulation of the biological functions performed by this particular cell. Failure to accurately localize cellular biomolecules is frequently associated with disease. In order to generate, maintain and modulate biogenesis, composition and location of various intracellular compartments, eukaryotic cells have developed sophisticated machineries to ensure transport of metals, metabolites, lipids, proteins, and nucleic acids across membranes and to support membrane trafficking within the cell. Work in the Research Cluster Cellular Compartmentation and its Relevance for Disease (Figure) is dedicated to the elucidation of the molecular mechanisms underlying various membrane transport and compartmentalization processes in eukaryotic cells using yeast, pathogenic fungi, human cell culture, and mice as model systems. Participating groups of Philipps University and the Max-Planck-Institute for Terrestric Microbiology analyze the mechanistic basis of the generation and maintenance of the intracellular compartmentation by using state-of-the-art technology including proteomics, genomics, live-cell and super-resolution imaging methods. The groups also exploit pathologically altered cells to analyze and compare the changes in the intracellular compartments in order to define and distinguish normal and pathologically altered processes at the molecular level. A unifying goal of the research groups in this area is the identification and characterization of the molecular machineries participating in the biogenesis, maintenance and dynamic alteration of the various compartments of a eukaryotic cell. Further, the groups try to unravel the mechanisms underlying the intracellular transport of proteins, nucleic acids, lipids, metabolites, and metals. Another central focus is on the impact of (highly pathogenic) viruses, intracellular parasites, and fungal pathogens on intracellular compartmentalization, and on the importance of compartment-specific tropism for pathogen reproduction and host cell toxicity. The common goal of these projects is the elucidation of how these pathogens alter and exploit cellular compartments to ensure their own survival. The thorough mechanistic investigation of the molecular basis of intracellular compartmentation is a prerequisite for the understanding of the disease-relevant phenotypes and the long-term development of therapeutic regimes. Recently, we have intensified the contacts to the Research Clusters of Tumor Biology and Immune and Infection Biology, since it has become evident that the problem of correct (sub-)cellular location also applies to these areas (Figure). Vice versa, the regulatory and signaling mechanisms studied within these two Clusters are of increasing interest for our area in order to understand how the cell maintains its overall homeostasis. As a consequence of these mutual interests in the two clusters, the participating research groups jointly address the regulation of the intracellular localization of proteins, RNA and lipids in healthy cells and after tumorigenic and infectious alterations. The signaling pathways leading to alterations in cellular compartmentation in response to changing physiological conditions or external challenges are also studied jointly. Our Research Cluster maintains intensive contacts to and collaborations with the faculties of Biology, Chemistry and Pharmacy, as well as the Max-Planck- Institute of Terrestrial Microbiology (Figure). Finally, we participate in the activities of the LOEWE Center of Synthetic Microbiology. 3

5 General Aspects Examples for research projects in this area: Analysis of the mechanisms of the intracellular vesicle transport and the molecular basis of cell polarization of, e.g., polarized epithelial cells Investigation of the role of mitochondria, cytosol and nucleus in the biogenesis of iron-sulfur proteins and the relevance for neurodegenerative, metabolic, and hematological diseases Analysis of the mechanisms of the intracellular transport, subcellular localization, membrane microcompartmentation of ion channels and lipids in the activation of signal-transducing processes (e.g., in caveolae) Investigation of various aspects of nucleo-cytoplasmic transport and protein und (micro)rna transport across biological membranes Study of transport processes between host cells and the malaria pathogen Plasmodium falciparum and its relevance for the lifecycle of the pathogen Investigation of the changes in intracellular compartmentation during the plant cell infection by pathogenic fungi Analysis of mechanisms how highly pathogenic viruses (Influenza, Marburg, Ebola, Lassa, Dengue etc.) exploit and alter the intracellular compartments (mainly the nucleus and secretory apparatus) for the own proliferation Diseases include Disorders of transport processes with relevance for tumor development Ion channel diseases Sugar transport diseases Neurological disorders associated with the erroneous trafficking of macromolecules involved in intracellular transport Hypertension Various iron storage diseases, myopathies and anemias, and diverse neurological diseases (Lowe-, Bartter- und Anderson-Syndrome, Friedreich Ataxia) with a primary defect in the intracellular compartmentation Mitochondrial fatal encephalopathies and myopathies with multiple metabolic disorders Plant infections by pathogenic fungi (smut) Various viral diseases such as influenza and hemorrhagic fever Fig. 1 Structure of the research cluster Cellular Compartmentation and its Relevance for Disease and its integration into the Marburg research land 4

6 General Aspects Research Cluster Clinical Immunology and Infection Biology The research focus area Clinical Immunology and Infection Biology is mainly concerned on the one hand with the immunopathogenesis of chronic inflammatory processes, among which rate autoimmune diseases and allergies on the other hand with the pathogenesis of viruses that cause severe disease. Starting point to investigate chronic inflammatory diseases was the awareness of a strong increase of these disease entities, particularly since the end of the Second World War and most of all in the industrialised regions of the world. The phenomenal increase in these illnesses cannot be explained solely by a genetic predisposition for the manifestation of the phenotype (gene-gene-interactions). The identification of protective or disease-promoting environmental influences from life style and diet have led to the so-called hygiene hypothesis, in whose further development there was crucial impact by research groups from Marburg. In the Transregional Collaborate Research Centre SFB/TR 22 Allergic immune responses of the lung (Speaker Prof. Renz) epidemiological evidence from international prospective cohorts provides the basis for generating hypothesis. On the one hand the focus is on immunological regulation processes and signal paths of the innate and acquired immune system. On the other hand failing signalling paths of resident cells of the lungs and the respiratory passages such as epithelia, fibroblasts and smooth muscle cells are investigated. Overall the consortium follows a translational research approach aiming to develop new concepts for prevention and to identify new therapeutic targets, which will be clinically evaluated later in the project. This research field is broadly established in the School of Medicine involving the Departments of Pneumology, Dermatology and Pediatrics as well as the Institutes of Immunology, Medical Microbiology and Clinical Chemistry. In 2009 the LOEWE-Centre UGMLC Universities Giessen and Marburg Lung Centre was granted in collaboration with the Max-Planck- Institute for Heart and Lung Research at Bad Nauheim, in which the joint activities to explore infectious, inflammatory-allergic and vascular pulmonary diseases were brought together. In the recently established German centre for lung illnesses (DZL) UGMLC is one of six national research centres for health. DZL has already taken up his research activities end of A main focus of the Marburg group within the DZL is the chronic inflammatory lung illnesses asthma and COPD. Marburg University has a long tradition in working with highly pathogenic viruses which goes back to the isolation and characterization of Marburg virus in Since then the focus of the Institute of Virology is to understand the biology and pathogenesis of agents like Ebola, Lassa, Nipah and influenza virus. The construction of facilities allowing to work safely with these viruses was of crucial importance. Since 2008 the Philipps-University operates a modern Biosafety level 4 (BSL-4) laboratory where highly pathogenic viruses can be investigated, without harming the scientists and the environment. Most of the highly pathogenic viruses are zoonotic and transmission from the animal host to humans causes severe illness. Understanding the viral and host factors that contribute to the severity of the disease course is important for developing novel antiviral strategies and effective vaccines. These investigations are funded by the collaborative research center SFB 593 (Speaker Prof. Lill, and SFB 1021 (Speaker Prof. Becker, the German Center for Infection Research (http://www.dzif.de/) as well as many grants from the European Union. The collaborative nature of these investigations becomes obvious by the fact that within the funded networks infection disease specialists work closely together with immunologists, cell biologists, clinical chemists, pharmaceutical chemists and biochemists from the faculty of medicine at the Philipps-University and other departments of the university. 5

7 General Aspects Fig.2 Organisation of the research cluster Clinical Immonology and Infection Biology Research Cluster Oncology and Tumor Biology In the research focus Oncology and Tumor Biology one of the main questions is, how oncogenic signaling, genetics and epigenetics interact to generate a cancer phenotype characterized by deregulation of proliferation control, invasive and metastatic growth, reprogramming of energy metabolism, and drug resistance. Current funding programmes are the Transregional Collaborative Research Centre SFB/TR17 Ras-dependent pathways in human cancer (Speakers: Prof. Eilers, Würzburg and Prof. A. Neubauer, Marburg) and the Clinical Research Unit KFO 210 Genetics of drug resistance in cancer (Speaker: Prof. A. Neubauer). In the Transregional Collaborative Research Centre SFB/TR81 Chromatin changes in differentiation and malignancies (Speaker: Prof. Renkawitz, Giessen) dynamic alterations of the chromatin structure (epigenetics) are at the forefront of research. Interactions between tumor cells and host cells in the microenvironment of the tumor, which significantly affect tumor growth and progression, are the focus of the LOEWE research cluster Tumor & Inflammation (Speaker: Prof. Müller). Research on tumor-host interactions will be further fueled by the new research building Center for Tumor and Immune Biology that is currently being built with funding from the BMBF and the State Hessen. Apart from this basic and translational research focus, the area of clinical oncology was continually and successfully developed. The central organizational platform of clinical oncology is the Marburg Comprehensive Cancer Center (CCC). A new building for patient care and patient-oriented clinical research was erected by means of the Carreras Leukemia Foundation (Carreras Leukämie Centrum, Speaker Prof. A. Neubauer). The Carreras Leukämie Centrum contains a Clinical Trial Unit, in which experimental phase I/II studies concerning new signal modulators are carried out in cooperation with the Marburg Coordination Centre for Clinical Studies (KKS). 6

8 General Aspects Oncology will be supplemented in research and clinic by a Particle Therapy Centre. For research tasks a professorship each for radiation biology and radiation physics will be established. Additional translational projects in the major research area tumor biology are concerned e.g. with the pancreatic carcinoma. Within the NGFNplus network Genome Network Pancreatic Carcinoma (Coordinator: Prof. T. Gress), the EU-network MolDiag-PaCa (Coordinator: Prof. T. Gress) and the national case data base Hereditary Pancreatic Carcinoma ( FaPaCa, Coordinator: Prof. D. Bartsch) the investigation of the molecular and genetic mechanisms of cancerogenesis in the pancreas of paramount interest and will serve as a basis for the development of new molecular target-oriented, diagnostic and therapeutic methods. Fig. 3 Structure of the research cluster Oncology and Tumorbiology 7

9 General Aspects Coordination Centre for Clinical Studies (KKS) Since the establishment of coordinating centres for clinical trials (KKS) by BMBF there is one of these centres at the department of medicine in Marburg. KKS Marburg started in Focus of the work of KKS is to increase the quality of clinical trials and the acceptance of clinical research in the academic environment and to implement the principles of "Good Clinical Practice" in everyday clinical practice. In 2005, all funded KKS in germany have formed a consortium (KKS Network). The network offers a wide range of scientific services on a regional and national basis to scientists in universities, hospitals and industry. Beyond the actual tasks in clinical research (trial planning, conducting and evaluation including publication of the trial results) KKS Marburg has taken over the following functions: Operating as sponsor for all investigator initiated trials with the principal investigator in Marburg Handling of all contracts dealing with patient oriented research. Deputy chair of the KKS network Chair of the working group data management and biometry of the KKS Network Member of the European consortium ECRIN (European Clinical Research Infrastructures Network and Biotherapy) Deputy chair of the working group management of clinical trials ot the TMF e.v. (Technologie und Methodenplattform für die vernetzte medizinische Forschung) Participation in hearing of experts on the amendment to Medical Devices Act (MPG) Member of the working group Medical Devices by the Health Research Council (Gesundheitsforschungsrat) The majority of supported clinical trails are investigator initiated trials. These trials are partly funded by the BMBF/DFG programm Clinical trials. KKS supports the investigators at the submission / call for proposals, conduct the trials and publishs the results in cooperation with the investigators. Coordinating Centre for Clinical Trials (KKS Marburg) Quality Management Contract Management Planning and Conduct of Clinical Trials Education Moduls Acting as Sponsor for CTs Contract design Biometrics Principal Investigator Genomics SOP-System Contract review Data Management and IT Systems Investigator Health Economics Auditing Preparation of contracts in multi-centre CTs Study Management and Monitoring Study Nurse Lung (UGMLC) Pharmacovigilance Fig. 4 Organisation chart of KKS Marburg 8

10 General Aspects Technology-Transfer by TransMIT The translational research approach, particularly of the clinically oriented research focus areas, leads to the generation of new knowledge and new technologies, whose innovative character has been recognised and whose intellectual authorship needs to be protected. For this purpose the TransMIT Society for Technology Transfer serves as the potential transfer facility for the middle Hessian universities and universities for applied science. TransMIT was awarded the first rank in the evaluation of all university-based transfer institutes in Germany (see also A number of university professors and lecturers from Marburg are involved in the TransMIT GmbH via TransMIT centres. The TransMIT GmbH is associated with the Hessian Intellectual Property Offensive (HIPO) alliance. Arising from this transfer of innovation the company sterna biologicals has been founded, which aims to use transcription factors as innovative targets for the treatment of chronic inflammations through the application of modern DNAzymtechnology (2nd place in the nationwide start-up competition Science4Life 2007). Research Funding An overview of total research funding of the School of Medicine from 2004 to 2012 is given in Table 1 and Fig. 5. This illustrates that the school has aquired considerable funding by being awarded three Collaborative Research Centres by the German Research Council. Overall third-party funding of the school in the last years amounts to around one third of the received state funding. During the last two years this percentage has considerably increased. Performance-Related Internal Funding There is no direct ex-post parameter-controlled and performance-related funding among the Medical Schools in the federal state of Hesse. Performance-related funding has been introduced at the School of Medicine at Marburg University following the recommendations of the German Research Council (DFG) from July 2004 on Performance- Related Funding (LOM) at Medical Schools. Thereby the same rules apply for all preclinical institutes, clinical-theoretical institutes and clinical departments. In the underlying assessment publication performance and acquired research funding are taken into account in equal proportions, extending over the past three years respectively. Thereby research funding granted after an external review process is taken into account in full. Research funding granted without an external review process, e.g. funding from industry, is taken into account with only 30 percent. Total expenditure of research funding per year is used for the calculation. Publication performance is quantified by the Journal Impact Factor (JIF) of the respective journal of all published original papers. Thereby firstand last autorship rate with one third of the JIF each, the remaining third of the JIF is divided between all middle authors. The amount of funding of an institute received in the annual LOM corresponds to its overall contribution in terms of publication performance and acquired funding in relation to all other evaluated institutes. Currently the different sizes of institutes are not considered in the assessment and do not enter into the calculation. From the year 2010 the school aims to introduce performance-related funding for teaching based on teaching assessments. Beyond this, in accordance with recommendations of the German Research Council, the school will enter into the concept of performance-related funding for the promotion of young researchers and into a performance-related allocation of research and office space (LOF). In the context of the LOF each institute will at first receive a parameter-based basic provision of research space (laboratory space). On a strictly temporary basis this basic provision of institutes will be supplemented by the dean s office taking into account proven research activities (e.g. third-party funded personnel). The re- maining research and office space will be allocated on a flexible basis by the dean s office for currently funded research projects. 9

11 General Aspects Year DFG DFG/SFB FRG EU State Sponsors Foundation Non-public Funding Behring/ Röntgen Foundation Funding by UKGM Total Funding Table 1 Development of research funding (in ) from 2004 to 2012 in different funding categories Research funding in extramural funding intramural funding Fig. 5 Development of total research funding from 2004 to

12 Preclinical Institutions Institute of Anatomy and Cell Biology Research Group Professor R. Kinscherf Prof. Dr. Wulf Hildebrandt; Prof. Dr. Beate Wilhelm; Dr. Gabriel A. Bonaterra; Dr. Hannes Kubo; Dr. Anja Schwarz; Dr. Stefanie Zügel Main fields of research Arteriosclerosis: Novel biomarkers in the blood Development and progression of Arteriosclerosis Role of GDF-15 in Arteriosclerosis Signal transduction of oxldl Obstructive sleep apnoea syndrome (OSAS): Microcirculatory and metabolic changes of skeletal muscles Signal transduction in tumor cachexia Molecular mechanisms of the anti-inflammatory, anti-proliferative and pro-apoptotic effects of phytopharmaka The plasma membrane Ca2+-ATPase 2 (PMCA2) in breast cancer Research projects Title Role of GDF-15 (Growth-Differentiation Factor- 15) in arteriosclerosis Principal investigator(s) R. Kinscherf Summary Growth-differentiation factor-15 (GDF-15) is a distant and divergent member of the transforming growth factor (TGF)-ß superfamily. GDF-15 expression is induced under inflammatory conditions and increased GDF-15 serum levels are suggested as risk factors for cardiovascular diseases. The aim of the study was to investigate the role of GDF-15 in arteriosclerosis using GDF-15 -/- mice crossbred with apoe -/- including a cholesterol-enriched diet. Funded by DFG (Ki 695/6-1) German Science Foundation Funding period Title Investigation of immunological and (anti)inflammatory effects of plant extracts and homeopatic components Principal investigator(s) R. Kinscherf Summary The medicinal product STW 11 (Influex ) contains the extract from purple coneflower, which is used in the prevention and therapy of infectious diseases. The aim of the study is to determine the effects of STW11 (Influex ) on maturation and expression of cytokines, chemokines, Toll-like receptors or antigen presentation in cultured mature or immature dendritic cells. Funded by Fa. Steigerwald Arzneimittelwerk GmbH Funding period Title Hepatic factors of tumor cachexia: Metabolom- Analyses, 31P-MR-Spectroscopy, as well as gene expression in perivenous and periportal hepatocytes and in Kupffer cells Principal investigator(s) R. Kinscherf, W. Hildebrandt, G. A. Bonaterra, M. Schäfer, V. Fendrich, A. Kießling Summary More than 50% of all tumor patients experience tumor cachexia (sarkopenia), which inversely influences quality of life and mortality. Early alterations of liver metabolism during sarcopenia especially the negative nitrogen balance are not clear. The aim of the study is to investigate the role of the liver during sarcopenia using an animal model, as well as human biopsies. Funded by UKGM University Medical Centre Giessen/Marburg Funding period Title Obstructive sleep apnoea syndrome (OSAS): Microcirculatory and metabolic changes of skeletal muscles Principal investigator(s) W. Hildebrandt, R. Schulz, U. Koehler, N. Weissmann Summary Hypoxia/Reoxygenation stress during obstructive sleep apnoea syndrome (OSAS) is suggested to be the reason for endothelial dysfunction and insulin resistance, which may result in loss of efficiency of heart and skeletal muscle. The aim of the study is to investigate molecular mechanisms of a reduced function of skeletal muscle during OSAS using an animal model, as well as human biopsies. Funded by von Behring-Röntgen-Foundation Funding period Title Investigation of the drug delivery concept of lipid-nucleoside- and polysaccharide-conjugates of 5- Fluorouracil Principal investigator(s) R. Kinscherf Summary Colon cancer is the third most commonly diagnosed malignancy in human beings, treated with the most commonly used drug in colon cancer chemotherapy, 5-flourouracil (5-FU). The aim of the study is to investigate the Drug Delivery concept of Lipid-Nucleoside- and Polysaccharide- conjugates of 5-Fluorouracil on proliferation, cytotoxicity, cell death and signalling using HT-29 colon carcinoma cells in vitro. Funded by B. Braun Melsungen AG Funding period Title Effects of anaplerotic substances on the citric acid cycle in human hepatoma (HepG2) and murine myoblast (C2C12) cell lines Principal investigator(s) R. Kinscherf 11

13 Preclinical Institutions Summary Anaplerosis is the re-filling of catalytic intermediates of the cycle that carry acetyl-coa as it is oxidized. The aim of the study is to investigate the effect of the anaplerotic medium-odd-chain triglyceride triheptanoin (in comparison with sodium-heptanoate, n-hexanoic acid sodium salt or n-octanoate) on key steps of the citric acid cycle in HepG2 cells. Funded by B. Braun Melsungen AG Funding period Title Protective effect of omega-3-fatty acids against the nephrotoxic side effect of Gentamicin or Ketorolac on kidney derived cells Principal investigator(s) R. Kinscherf Summary Gentamicin is a nephrotoxic aminoglycoside antibiotic and ketorolac is an antiinflammatory drug. Omega-6 and omega-3 polyunsaturated fatty acids are precursors of potent lipid mediators, playing an important role in the regulation of inflammation. The aim of the in vitro investigation is to determine the possible protective effects of omega-3 on kidney derived-cells against the nephrotoxic effects of gentamicin or ketorolac. Funded by B. Braun Melsungen AG Funding period Most important publications Kassner SS, Schöttler S, Bonaterra GA, Stern-Sträter J, Sommer U, Hormann K, Kinscherf R**, Gössler UR** (2011). Proinflammatory and proadhesive activation of lymphocytes and macrophages in sudden sensorineural hearing loss. Audiol Neurootol 16(4): **senior authors Brandenburger T, Strehler EE, Filoteo AG, Caride AJ, Aumüller G, Post H, Schwarz A, Wilhelm B (2011) Switch of PMCA4 splice variants in bovine epididymis results in altered isoform expression during functional sperm maturation. J Biol Chem 286(10): Stern-Straeter J, Bonaterra GA, Kassner SS, Zügel S, Hörmann K, Kinscherf R**, Goessler UR** (2011) Characterization of a human myoblast differentiation for tissue-engineering purposes by quantitative gene expression analysis. J Tissue Eng Regen Med 5(8): e **senior authors Schober A, Parlato R, Huber K, Kinscherf R, Hartleben B, Huber TB, Schütz G, Unsicker K (2012) Cell loss and autophagy in the extra-adrenal chromaffin organ of Zuckerkandl are regulated by glucocorticoid signalling. J Neuroendocrinol 2012 Aug 1. doi: /j x. [Epub ahead of print] Streitner I, Goldhofer M, Cho S, Kinscherf R, Thielecke H, Borggrefe M, Süselbeck T, Streitner F (2012) Cellular imaging of human atherosclerotic lesions by intravascular electric impendance spectroscopy. PLoS One 7(4):e Epub 2012 Apr 11 Aumüller G, Doll A, Wennemuth G, Dizeyi N, Abrahamsson PA, Wilhelm B (2012) Regional distribution of neuroendocrine cells in the urogenital duct system of the male rat. The Prostate 72: Friedmann-Bette B, Schwartz FR, Eckhardt H, Billeter R, Bonaterra G, Kinscherf R (2012). Similar changes of gene expression in human skeletal muscle after resistance exercise and multiple fine needle biopsies. J Appl Physiol 112(2): Phillips B, Williams J, Atherton PJ, Smith K, Hildebrandt W, Rankin D, Greenhaff PL, Macdonald IA, Rennie M (2012) Resistance exercise training improves age-related declines in leg vascular conductance and rejuvenates acute leg blood flow responses to feeding and exercise. J Appl Physiol 112(3): Total Impact Factor 36.3 Honours /Awards Elected president of the German Atherosclerosis Society Ralf Kinscherf Elected Member of faculty council of the Philipps- University of Marburg Ralf Kinscherf TransMit Project Division for Cellular Signaling Head: R. Kinscherf W. H. Hauss Award of the German Atherosclerosis Society for Dr. Stefanie Zügel for the publication Growth differentiation factor-15 (GDF-15) deficiency inhibits atherosclerosis progression by regulating IL-6 dependent inflammatory response to vascular injury. (R. Kinscherf, senior author). Research Group Professor E. Weihe PD Dr. Michael Bette; Dr. Mirjam Bertoune (Preuss); PD Dr. Burkhard Schütz; Dr. Martin K.-H. Schäfer; PD Dr. Reiner Westermann Main fields of research Chemical coding of neurotransmission and neuroendocrine secretion Molecular and cellular mechanisms of preclinical and clinical pain Inflammation Neuroinfection (rabies, HIV/SIV encephalitis) Neuroimmune interactions and neurodegeneration (amyotrophic lateral sclerosis; Parkinson s disease) 12

14 Preclinical Institutions Neuropeptide signaling and pathophysiology; biological effects of ozone in cancer research Specialities: Core facility for molecular histology and laser microdissection (Schäfer/Weihe); cellspecific gene expression profiling; transgenic mouse models relevant for research on infection, inflammation, pain, cancer, diabetes and neurodegeneration Research projects Title Regulation of the cholinergic gene locus in keratinocytes Principal investigator(s) B. Schütz and E. Weihe Summary The cholinergic gene locus (CGL) encodes two genes for proper cholinergic neuron function, i.e. choline acteyltransferase (ChAT) needed for the production of acetylcholine (ACh), and the vesicular acetylcholine transporter (VAChT) for regulated import of ACh into synaptic vesicles. We hypothesize that the transcriptional regulation of the CGL in the production and sequestration of keratinocyte ACh essentially differs from that found in neurons. In our project we thus aim to elucidate the regional, skin layer- and cell-specific activity of the CGL under physiological and pathophysiological situations (e.g. Inflammation, barrier function disturbances) in humans and rodent (mouse, rat) model systems, and the possibility of CGL regulation by exogenously applied substances using state of the art technologies (e.g. laser capture microdissection, qrt-pcr, in situ hybridization, transcriptome profiling). Funded by LOEWE-Research Focus Giessen, Marburg, Frankfurt, Non-neuronal cholinergic Systems, Project B3 Funding period Title German Lung Center (Deutsches Lungenzentrum, DLZ Principal investigator(s) E. Weihe Summary The aim is to decipher the neuroimmune anatomy and role of neuropeptide and classical transmitter signaling in inflammatory and allergic airway diseases by using neuropeptide and neuropeptide receptor gene deficient mouse models (gene deficiencies for PACAP, PAC1, CGRP, RAMP1) and experimental stress conditions. Funded by BMBF Federal Ministry of Education and Research Funding period Title Muscular versus neuronal M2- and M4- receptors in the respiratory tract. Modulating role of neuronal muscarinic and PACAP receptors in the cholinergic airway contraction Principal investigator(s) E. Weihe, W. Kummer, Braun Summary Using high resolution in situ hybridization and immunocytochemistry. The project was aimed to determine the neuronal and non neuronal tracheobronchial expression patterns of subtypes of muscarinic receptors and of receptors and ligands of the VIP/PACAP family Funded by LOEWE Center UGMLC Funding period , Title Validation of a new medical technical device for cancer therapy Principal investigator(s) M. Bette, E. Weihe, J. Werner and R. Mandic Summary Focus of this grant is to analyze the therapeutic potential of an alternative canter therapy including the cellular and molecular mechanisms including to reason is appropriate for mechanism. The aim is to grade up an existing patent on the therapeutic schema. Funded by Infrastrukturbank Hessen Funding period Title Role of immunoregulatory neuropeptides in rabies virus infection Principal investigator(s) E. Weihe Summary This project is based on the hypothesis that the neurotropic rabies virus subverses efficient immune responses in the CNS by inducing immunoregulatory neuropeptides like CGRP and adrenomedullin and stimulating their release. Funded by LOEWE Research Focus Changes of viral pathogenicity in host switch and persistent infection Funding period Title Immunoregulatory role of cerebral TLR & cytosolic RNA sensors during neurotropic virus infection Principal investigator(s) M. Bertourne and E. Weihe Summary Aim of this project was to analyze the involvement and cellular localisation of pattern recognition receptors in the CNS, with special focus on TLR3 and RIG-I, during infection with rabies virus strains of various pathogenicity. Funded by UKGM University Medical Centre Giessen/Marburg Funding period Title VMAT2 as a target for imaging of beta-cell mass Principal investigator(s) E. Weihe and M. Schäfer Summary The main aim of the project was to evaluate species-specific expression patterns of the vesicular monoamine transporter 2 (VMAT2) in primate, pig and rodent pancreatic beta-cells, nerves, and mast cells and to generate a new transgenic mouse model for beta-cell imaging with tetrabenazine based VMAT2 radioligands. Funded by EU (FP7/ ) Funding period Title Role of neuropeptides in tumor-host interaction Principal investigator(s) E. Weihe and M. Schäfer 13

15 Preclinical Institutions Summary The project aimed to decipher neuropeptide PACAP signaling in lung tumor cells. Funded by LOEWE Research Focus Tumor and Inflammation Funding period Title Laser Microdissection Core Facility Principal investigator(s) E. Weihe and M. Schäfer Summary The project provides a platform for cell specific gene expression analysis of tumor cells and specific cells of the tumor microenvironment. Funded by LOEWE Research Focus Tumor and Inflammation Funding period Title Pathogenetic role of beta-calcitonin generelated peptide gene-deficiency in the SOD1 mouse model of ALS Principal investigator(s) B. Schütz Summary This project is based on the hypothesis that the communication between motor neurons and glial cells is disturbed during disease progression in ALS, and that beta-cgrp may play a role in this process. Therefore, a beta-cgrp knockout is placed into the SOD1 mouse model of ALS and the resulting phenotype analyzed on the behavioral, cellular and molecular levels in comparison to SOD1 mice with functional beta-cgrp. Funded by German Society for Muscle diseases - SC10/4 Funding period Title Impact of paracrine released cytokines for the remodeling of the insufficient heart Principal investigator(s) R. Maxeiner, Wentzel and M. Bette Summary Aim of this project is to proof the hypothesis that human cadial progenitor cells (CPC) exhibit it s therapeutic potential on remodeling and regeneration of the heart by the release of several cytokines. Main factors, identified by its potential to positively influence cardiac muscle contraction in vitro, are GDF-15, IL-6, IL-8, TIMP-1, and MCP-1. The impact of these factors on remodeling of the heart and on hypertension should be characterized in an in vivo rat model. Funded by Von-Behring-Röntgen Foundation Funding period Title Influence of the gene deficiency for calcitoningene related peptide alpha and pituitary adenylate cyclase activating peptide on the in vivo rabies virus infection Principal investigator(s) Betourne Summary Aim of the project is to elucidate mechanisms for the biological effect of CGRPa and PACAP during infection with rabies virus in the mouse model. Funded by UKGM University Medical Centre Giessen/Marburg Funding period Title Characterization of an astrocyte population susceptible for rabies virus Principal investigator(s) Betourne Summary Aim of the project is to identify the molecular prerequisites that make a regionally defined population of fibrillary astrocytes in the murine brain vulnerable to a mutated rabies virus vaccine strain. Funded by Kempkes Foundation Funding period Title Involvement of peptidergic signaling pathways in ALS pathogenesis in human patients Principal investigator(s) C. Ringer Summary The disruption of the signaling pathways of PACAP and CGRP by genetic depletion resulted in a decelerated disease progression in the SOD1 mouse model of ALS. This study investigates if the two neuropeptides also influence ALS disease progression in humans. Funded by Kempkes Foundation Funding period Title Mechanisms responsible for the selective vulnerability of CGRP expressing motoneurons in amyotrophic lateral sclerosis Principal investigator(s) C. Ringer Summary This study is based on the observation, that motoneurons expressing the neuropeptide CGRP selectively degenerate, whereas motoneurons without CGRP expression seemed to be resistant in the SOD1 mouse model of ALS. The aim is to clarify the underlying mechanisms of neuronal vulnerability and resistance, respectively, to ALS pathology. Funded by German Society for Muscle diseases Funding period Title Chemical phenotyping of striatal tyrosine hydoxylase positive Interneurons by laser microdissection Principal investigator(s) Klietz, M. Schäfer and E. Weihe Summary Project and Travel Grant Funded by Medizin-Stiftung Marburg Funding period Most important publications Depboylu C, Schäfer MK, Arias-Carrión O, Oertel WH, Weihe E, Höglinger GU (2011) Possible involvement of complement factor C1q in the clearance of extracellular neuromelanin from the substantia nigra in Parkinson disease. J Neuropathol Exp Neuro 70(2):

16 Preclinical Institutions Depboylu C, Weihe E, Eiden LE. COX1 and COX2 expression in non-neuronal cellular compartments of the rhesus macaque brain during lentiviral infection (2011) Neurobiol Dis (1): Krasteva G, Canning BJ, Hartmann P, Veres TZ, Papadakis T, Mühlfeld C, Schliecker K, Tallini YN, Braun A, Hackstein H, Baal N, Weihe E, Schütz B, Kotlikoff M, Ibanez-Tallon I, Kummer W (2011) Cholinergic chemosensory cells in the trachea regulate breathing. Proc Natl Acad Sci U S A 108(23): Depboylu C, Schorlemmer K, Klietz M, Oertel WH, Weihe E, Höglinger GU, Schäfer MK (2011) Upregulation of microglial C1q expression has no effects on nigrostriatal dopaminergic injury in the MPTP mouse model of Parkinson disease. J Neuroimmunol 236(1-2):39-46 Ringer C, Weihe E, Schütz B (2012) Calcitonin generelated peptide expression levels predict motor neuron vulnerability in the superoxide dismutase 1- G93A mouse model of amyotrophic lateral sclerosis. Neurobiol Dis 45(1): Depboylu C, Weihe E, Eiden LE (2012) Lentiviral infection of rhesus macaques causes long-term injury to cortical and hippocampal projections of prostaglandin-expressing cholinergic Basal forebrain neurons. J Neuropathol Exp Neurol 71(1):15-27 Krasteva G, Hartmann P, Papadakis T, Bodenbenner M, Wessels L, Weihe E, Schütz B, Langheinrich AC, Chubanov V, Gudermann T, Ibanez-Tallon I, Kummer W (2012) Cholinergic chemosensory cells in the auditory tube. Histochem Cell Biol 137: Holighaus Y, Weihe E, Eiden LE (2012) STC1 Induction by PACAP is mediated through camp and ERK1/2 but not PKA in cultured cortical neurons. J Mol Neurosci 46:75-87 Total Impact Factor 62.4 Honours /Awards Steering Committee member of LOEWE Research Focus Non-Neuronal Cholinergic Systems Univ. Giessen/Marburg/Frankfurt E. Weihe Vice Director of the Center for Tumor & and Immune Biology (CTI) Marburg E. Weihe Editorial Board Member: Cellular and Molecular Neurobiology; Journal of Molecular Neuroscience; Journal of Experimental Neuropathology and Experimental Neurology; Neurochemistry International; Neurobiology of Disease E. Weihe Editorial Board Member Immunobiology M. Schäfer TransMit Project Division PainOmics Project leaders: E. Weihe & M. Schäfer Non-executive CEO of Pharmnovo, Gothenburg, Sweden E. Weihe Member of the International Advisory Board of the 10th International Catecholamine Symposium September 9-13, 2012 Pacific Grove, California E. Weihe Scientific Advisor of the 10th International Symposium on VIP, PACAP and Related Pepides, December 13-16, 2011, Eilat, Israel E. Weihe Member of Steering Committee of the German Brain Immune Network (GEBIN) E. Weihe Board Member of the Graduiertenzentrum Lebensund Naturwissenschaften, Philipps-University Marburg M. Bertoune Elected Member of the Senate of Philipps-University Marburg M. Schäfer, E. Weihe President of the committee) according to 15 of the law of animal protection at the regional council Giessen M. Bette Research group Professor Y. Cetin Main fields of research The working group is studying the functional role of the bioactive peptide guanylin in several organs). This peptide, originally isolated from the intestine, is meanwhile one family member of various guanylinrelated peptides including guanylin, uroguanylin, renoguanylin or lymphoguanylin. All peptides display sequence homologies and act in a very similar way. These guanylin-peptides regulate electrolyte/water secretion in various epithelia with signaling and effector proteins including guanylin-receptor guanylate cyclase C (GC-C), cystic fibrosis transmembrane conductance regulator (CFTR-) protein, cgmp-dependent Proteinkinase GII (cgkii), and at least an anion exchanger type 2 (AE-2). The best studied peptide is guanylin which is mostly produced by the epithelial cells and the affiliated signaling and effector proteins are localized to the apical membrane of the respective cells. Research projects Title Guanylin and functional coupling proteins in the hepatobiliary system of rat and guinea pig Principal investigator(s) K. Schwabe and Y. Cetin Summary Guanylin, GC-C, cgkii, CFTR, and AE-2 are expressed in liver and gallbladder as verified by RT- PCR and Western blot analyses. Immunohistochemical studies could localize guanylin and its affiliated signaling and effector proteins to the bile 15

17 Preclinical Institutions ductal cells in the liver and to the gallbladder epithelial cells, all confined exclusively to the apical membrane of the same epithelial cells. We assume that guanylin is synthesized in the hepatobiliary system and released luminally into the hepatic and cystic bile to regulate electrolyte secretion. Title Expression and cellular localization of guanylin and uroguanylin and their functional coupling proteins in the rat kidney Principal investigator(s) K. Schwabe & Y. Cetin Summary The expression of guanylin, uroguanylin, GC-C, cgkii, CFTR, and AE-2 in the rat kidneys was verified by RT-PCR and Western blot analyses. Guanylin and uroguanylin and their its affiliated signaling and effector proteins were localized by immunohistochemistry to distinct segments of the tubular system in the kidneys. We assume that guanylin and uroguanylin are expressed in the kidney and released into the tubules where they regulated electrolyte secretion Title Cyclic nucleotide-gated channels (cngs): expression and cellular localization in digestive organs Principal investigator(s) T. Leitl and Y. Cetin Summary Cngs are ion channels involved in intracellular Ca+ accumulation. These channels are regulated by cyclic nucleotides. RT-PCR and Western blotting analyses yielded expression of the cngisoforms cng 1 and cng 4 in stomach, intestine, liver, and pancreas of rat and guinea pig. In these organs both proteins were localized to the surface epithelial cells in stomach and intestine, to the ductal cells in the exocrine pancreas and to the bile ductal cells in the liver. Based on these findings we assume that cngs are involved in Ca+ transport in the respective epithelia. Most important publications Schwabe K, Cetin Y (2012) Guanylin and functional coupling proteins in the hepatobiliary system of rat and guinea pig. Histochem Cell Biol 137(5): Total Impact Factor 2.6 Research group Professor J. Seitz Main fields of research Our goal is the investigation of unconventional defense mechanism against microbes. Our main focus is the epididymis of rodents. Due to the bloodepididymis barrier only components of the innate immune system are able to act in the epididymis. Infections of the urinary tract may lead to severe spreading to epididymis. Therefore it is necessary to protect spermatozoa especially in genital tract organs by unspecific immune responses. Antimicrobial peptides, such as defensines, are known to be present in the genital organs. We are attempting to investigate a further small antimicrobial peptide called buforin. Primarily, buforin has been detected in the stomach of the toad. During exocytosis it is processed by proteolytic cleavage of histone H2A. Recent papers specify this new antimicrobial peptide as a highly effective bactericidal and fungicidal substance. It is also known to be active against cancer cells. Research projects Title Extracellular histone derivates in the epididymis of mice Principal investigator(s) U. Träger & G. Jennemann Summary We use a custom-designed antibody against buforin (BioGenes) to perform an immunohistochemical screening on paraffin sections of several mouse tissues with focus on male sexual organs like testis, epididymis, prostate, and seminal vesicle. Specificity of our custom-designed antibody was confirmed by western blot analysis. Most important publications Träger U, Homberg U (2011) Polarization-sensitive descending neurons in the locust: connecting the brain to thoracic Ganglia. J Neurosci 31: Dastig S, Nenicu A, Otte DM, Zimmer A, Seitz J, Baumgart-Vogt E, Lüers GH (2011) Germ cells of male mice express genes for peroxisomal metabolic pathways implicated in the regulation of spermatogenesis and the protection against oxidative stress. Histochem Cell Biol 136: Total impact factor 9.6 Research group Professor B. Steiniger Main fields of research Cell kinetics of the monocyte-macrophage system in rats Phenotype of lymphocytes, dendritic cells, endothelia and stromal cells in primary in secondary lymphatic organs in humans Cell composition of the human dental pulp and bone marrow Research projects Title Three-dimensional reconstruction of microvessels in human spleens 16

18 Preclinical Institutions Principal investigator(s) B. Steiniger Summary Capillary and sinus endothelia differ by immunohistological phenotype in human splenic red pulp. In three-dimensional models of the microvasculature no connections were found between red pulp capillaries and venous sinuses. Arterial microvessels exhibited open trumpetshaped endings. Thus, it is very likely that the human splenic red pulp harbours an entirely open circulation system, where the blood percolates through the reticular connective tissue before entering the sinuses. Title Composition of germinal centres in human tonsils and spleens Principal investigator(s) B. Steiniger Summary Full-blown germinal centres in hyperplastic tonsils consist of a dark zone, a basal and an apical light zone, and an outer zone surrounded by a mantle zone of small migratory naive B cells. In tonsils the outer zone is only present in certain germinal centres. Follicular dendritic cells (FDCs) occupy the entire germinal centre including the mantle zone. However, their phenotype and morphology varies in the different zones. In most adult spleens germinal centres are more quiescent than in tonsils. Title Stromal cells of T- and B-cell regions in human spleens Principal investigator(s) B. Steiniger Summary The arrangement of follicular dendritic cells and of phenotypically different populations of fibroblastic reticulum cells in the T-cell regions of human spleens is analyzed by immunohistology. Title Microscopic anatomy of the human bone marrow Principal investigator(s) B. Steiniger Summary In cooperation with the clinics of orthopaedics and of orofacial surgery and with Prof. Dr. V. Stachniss (formerly clinics of conservative dentistry) a special procedure was developped for embedding large bone marrow specimens (femoral head, iliac crest) in a special methacrylate. Nondecalcified sections are then cut with a microtome. The embedding plastic is removable and the sections can thus be processed for immunohistological staining. Different populations of immunocompetent and haematopoietic cells, stromal cells and endothelia are visualized. The three-dimensional arrangement of vessels and stromal cells is going to be reconstructed from serial sections. Comprehensive embedding and reconstruction techniques may finally permit to survey the marrow of an entire human femoral head. Immunohistological demonstration of CD34 (blue) in capillary endothelia and CD141 (brown) in sinus endothelia of human femoral bone marrow in an undecalcified methacrylate section. In contrast to fat marrow, haematopoietically active bone marrow areas contain two different types of microvessels Most important publications Steiniger B, Trabandt M, Barth PJ (2011) The follicular dendritic cell network in secondary follicles of human palatine tonsils and spleens. Histochem Cell Biol 135: Steiniger B, Bette M, Schwarzbach H (2011) The open microcirculation in human spleens: a threedimensional approach. J Histochem Cytochem 59: Total impact factor 5.3 General information about the institute Research funding ,28 Number of completed MD theses 3 Number of completed PhD theses 5 Contact Details: Robert-Koch-Str. 8, Marburg, Tel.:++49 (0) Director: Professor Dr. Eberhard Weihe 17

19 Preclinical Institutions Institute of Molecular Biology and Tumorbiology Research Group Professor Müller and the associated junior research groups of Dr. Matthias Lauth and Dr. Florian Heyd Main fields of research Rolf Müller s research projects address the regulation and function of the nuclear receptor and transcription factor PPARβ/δ in tumorigenesis and inflammatory cells with a focus on the chromatinbased mechanisms involved in these processes. Mathias Lauth s work is centered on the regulation and role of the Hedghog signaling pathways in tumor cells and their crosstalk with the tumor stroma. The group of Florian Heyd addresses the regulation of alternative splicing during T cell activation and the role alternative splicing plays to control T cell function. Another project deals with the regulation of the circadian rhythm by the splicing factor U2AF26. Research projects Title Regulation and function of PPARβ/δ in tumor stroma cells Principal investigator(s) R. Müller Summary Previous work by the group has identified an unexpected role for the nuclear receptor and transcription factor PPARβ/δ in tumor stroma organization. The aim of this project now is to investigate the role and regulation of PPARβ/δ in tumor progression with a focus on cancer cell invasion (Collaboration with Dr. Dominique Brandt and Robert Grosse, Institute of Phramacology). Essential tools for this work are novel inhibitory PPARβ/δ ligands we have developed in cooperation with the group Prof. Wibke Diederich at the Institute of Pharmaceutical Chemistry. Funded by DFG (SFB/TRR17) German Science Foundation, Transregional Collaborative Research Centre 17 Funded period Title Chromatin regulation by the nuclear receptor PPARbeta/delta Principal investigator R. Müller Summary The ligand-regulated nuclear receptor PPARβ/δ can both activate and repress transcription, but the regulation, mechanistic principles and biological consequences of these functions are only partly understood. By using a combination of chromatin immunoprecipitation (ChIP) sequencing and transcriptional profiling we have defined distinct types of transcriptional responses of target genes to PPARβ/δ ligands or PPARβ/δ depletion. Elucidation of the molecular basis of these distinct target gene responses is the goal of this project. Funded by DFG Funding period Title Regulation and function of PPARβ/δ in macrophages Principal investigator(s) R. Müller Summary Several lines of evidence clearly suggest a role for PPARβ/δ in different type of inflammatory cells of both the innate and the adaptive immune system. The aim of this project is to investigate the role and regulation of PPARβ/δ in myeloid cell differentiation and macrophage polarization and to unravel the crosstalk of PPARβ/δ with cytokine signaling pathways. Funded by LOEWE Funded period Title Function and therapeutic potential von PPARβ/δ in tumor-associated macrophages in human ovarian carcinoma Principal investigator S. Müller-Brüsselbach Summary Ovarian cancer is typically accompanied by the occurrence of malignant ascites containing large number of macrophages. It has been suggested that these tumor-associated macrophages (TAMs) are skewed to alternative polarization and thereby play an essential role in therapy resistance and metastatic spread. In this project, we investigate the nature, regulation and clinical correlations of TAM polarization in high grade serous ovarian cancer (collaboration with Dr. Silke Reinartz and Prof. Uwe Wagner, Clinic for Gynecology). A major focus of this work is on PPARβ/δ and its potential as a pharmacological target. Funded by Sander Foundation Funding period Title Mechanisms of Hedgehog signal transduction in tumor stromal cells Principal investigator(s) M. Lauth Summary The aim of this project has been to identify novel components in the Hedgehog signaling cascade which either function to transmit the ligandinduced signal or to mediate cross-talk to other signaling systems. A particular focus is on Hedgehogregulated protein transport processes involving the primary cilium, a cellular organelle with environmental sensing tasks. Funded by LOEWE Funded period

20 Preclinical Institutions Title Regulation of Hedgehog signaling by the Dyrk1B kinase Principal investigator(s) M. Lauth Summary The aim of this project has been to investigate how the tumor-associated Dyrk1B kinase affects mammalian Hedgehog signaling. The group could show that Dyrk1b functions as a negative regulator of the pathway. Furthermore, a molecular framework and a pathophysiological function for this interaction could be established. Funded by DFG GermanScience Foundation Funded period Title Evaluation der DYRK1A Kinase als anti-tumor Zielstruktur in der Behandlung des Pankreaskarzinoms Principal investigator M. Lauth Summary Previous work suggests an oncogenic role of the DYRK1A kinase in Hedgehog-driven malignancies. In the present project, our group investigates the molecular mechanisms of the Hedgehog-DYRK1A relationship and the impact of this crosstalk on the pathway activity in normal and in cancer cells. Funded by Deutsche Krebshilfe Funding period Title Funktionelle Konsequenzen von alternativen Spleißen in T-Zellen Principal investigator F. Heyd Summary In previous work we have used RNA-Seq to identify exons that are alternatively spliced upon T cell activation. The present goal of our group is to analyze the functionality of some of these splicing events in order to investigate the impact of alternative splicing on T cell activation. In particular we are analyzing splicing events that control the production and secretion of cytokines/chemokines as these are fundamental processes in T cell biology, which are, as we can show with our work, controlled by alternative splicing. Funded by DFG German Science Foundation Funding period Title The regulation of Traf3 alternative splicing in T cells and its role in signaling and cancer Principal investigator Florian Heyd together with Rotem Karni, Hebrew University, Jerusalem Summary Traf3 is expressed in several isoforms which either activate or inhibit the non-canonical NFkB pathway. The misregulation of this signaling pathway has been shown to be associated with malignant transformation. We are investigating a link between Traf3 alternative splicing, the activity of the non-canonical NFkB pathway and malignant transformation by characterizing the mechanism that controls Traf3 alternative splicing as well as the oncogenic potential of distinct Traf3 isoforms. Funded by Fritz Thyssen Foundation Funding period Title Analyse alternativer Spleißvorgänge und funktioneller Auswirkungen im Gehirn U2AF26- defizienter Mäuse Principal investigator F Heyd Summary The splicing factor U2AF26 is highly expressed in brain and is itself alternatively spliced. We were able to show that U2AF26 alternative splicing changes in a circadian manner and we are now investigating a role of the different U2AF26 isoforms in controlling the circadian rhythm. We have generated U2AF26 deficient mice that we are using to characterize clock-defects at the molecular level as well as in behavioral tests. Funded by UKGM University Medical Centre Giessen / Marburg Funding period Most important publications AG Müller Naruhn S, Toth PM, Adhikary T, Kaddatz K, Pape V, Dörr S, Klebe G, Müller-Brüsselbach S, Diederich W, Müller R (2011) High affinity PPARβ/δ-specific ligands with pure antagonistic or inverse agonistic properties. Mol Pharmacol 80: Adhikary T, Kaddatz K, Finkernagel F, Schönbauer A, Meissner W, Scharfe M, Jarek M, Blöcker H, Müller- Brüsselbach S, Müller R (2011) Genomewide analyses define different modes of transcriptional regulation by peroxisome proliferator-activated receptor-β/δ (PPARβ/δ). PLoS ONE 6(1): e16344 Stockert J, Adhikary T, Kaddatz K, Finkernagel F, Meissner W, Müller-Brüsselbach S, Müller R (2011) Reverse crosstalk of TGFβ and PPARβ/δ signaling identified by transcriptional profiling. Nucl Acids Res 39: Lieber S, Scheer F, Meissner W, Naruhn S, Adhikary T, Müller-Brüsselbach S, Diederich W Müller R (2012) (Z)-2-(2-bromophenyl)-3-{[4-(1-methylpiperazine)-amino]phenyl}acrylonitrile (DG172): an orally bioavailable PPARβ/δ-selective ligand with inverse agonistic properties. J Med Chem 55: Toth PM, Naruhn S, Pape V, Dörr SMA, Klebe G, Müller R, Diederich WE (2012) Development of improved PPARβ/δ inhibitors. ChemMedChem 7: AG Lauth Fendrich V, Oh E, Bang S, Karikari C, Ottenhof N, Bisht S, Lauth M, Brossart P, Katsanis N, Maitra A, Feldmann G. (2011) Ectopic overexpression of sonic hedgehog (shh) induces stromal expansion and 19

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