TRR 19:  Inflammatory Cardiomyopathy - Molecular Pathogenesis and Therapy

Area of Research is the Dilatated Cardiomyopathy (DCM), a heart muscle disease characterised by left and right ventricular dysfunction and dilatation. DCM is alongside coronary heart disease (CHD) the most frequent cause of heart failure. About 30% of patients develop heart failure as a consequence of DCM. In Germany about 500 000 patients suffer from DCM. Because of the high clinical relevance of the disorder there is an urgent need to develop new diagnostic and therapeutic procedures. The importance of DCM is also illustrated by the fact that alongside CHD it constitutes the main indication for heart transplantation (HTX).
According to recent research myocardial inflammation and/or viral infection (= Inflammatory Cardio-myopathy, DCMi) is the most frequent cause of DCM. Despite new pharmacotherapeutic approaches towards heart failure the 5-year-mortality of DCM is still higher than 50%, but currently there are no generally accepted therapeutic guidelines for DCMi. For most patients HTX is the only accepted palliative thera-peutic option beyond symptomatic heart failure therapy.
The general research goals in the subareas A-C are:
-- elucidation of structural determinants of DCMi at the cellular and molecular level
-- characterisation of virus-host-interactions and their relevance for the course of DCMi
-- development of new experimental and clinical therapeutic approaches building upon new findings from A and B
Goals in detail:
-- elucidation of exogenous and genetic determinants for the highly variable susceptibility for myocardial virus infections
-- detailed understanding of the rapid and potentially reversible "remodelling" of the myocardium during viral infections
-- elucidation of the immune mechanisms which, dependent on viral and host-specific pathogenicity factors, determine the course of the disease
-- development, evaluation, and possible clinical implementation of new experimental and clinical therapeutic procedures
-- further development of novel therapeutic approaches which may have therapeutic implications for cardiovascular medicine beyond the specific target disease of DCMi (RNA-based and gene therapeutic strategies etc.)
-- development of new genetic animal models (conditional tissue-specific knockouts etc.) for the evaluation of new therapeutic strategies and other purposes

DFG Programme CRC/Transregios

• A01 - Analysis of the Coxsackievirus-Adenovirus-Receptor (CAR) in the Pathogenesis of Cardiomyopathies (Project Heads Gotthardt, Michael ;  Poller, Wolfgang )
• A02 - Molecular Mechanisms of Matrix Remodeling in Inflammatory Cardiomyopathy (Project Heads Schultheiss, Heinz-Peter ;  Westermann, Dirk )
• A03 - The Relevance of Myocardial Tissue Factor Expression for the Structural Integrity and Cardiac Contractility in Inflammatory Cardiomyopathy (Project Head Rauch-Kröhnert, Ursula )
• A04 - Transkriptionelle regulatorische Netzwerke bei inflammatorischen Kardiomyopathien und ihre therapeutischen Implikationen (Project Heads Orzechowski, Hans-Dieter ;  Paul, Martin )
• A05 - Relevance of Parvovirus B19 (B19) Receptors and B19 Latency in the Pathogenesis of Cardioendothelial B19 Infections (Project Heads Fechner, Henry ;  Weger, Stefan )
• A06 - EMMPRIN (CD147): A Key Protein in the Regulation of Remodeling Processes in Inflammatory Cardiomyopathy? (Project Heads Gawaz, Meinrad Paul ;  May, Andreas E. )
• B01 - Einsatz molekularer Bibliotheken zur Identifizierung von T-Zellepitopen im Proteom von Myokarditis induzierenden Enteroviren am Beispiel des Coxsackievirus B3 (Project Heads Kern, Florian ;  Volkmer, Rudolf )
• B02 - Bedeutung von klonalen T-Zell-Expansionen und funktionellen T-Zellveränderungen bei Myokarditis und dilatativer Kardiomyopathie für die Pathogenese, Prognose und den Verlauf immunmodulatorischer Therapien (Project Heads Hummel, Michael ;  Noutsias, Michel ;  Volk, Hans-Dieter )
• B03 - Role of Proteasomes in Acute and Chronic Enterovirus Myocarditis (Project Heads Beling, Antje ;  Kloetzel, Peter Michael ;  Kuckelkorn, Ulrike )
• B04 - Functional Relevance and Immunoregulation of Natural Killer Cells in Acute and Chronic Enterovirus Myocarditis (Project Heads Klingel, Karin ;  Kotsch, Ph.D., Katja )
• B05 - Parvovirus B19-Associated Inflammatory Cardiomyopathy: Molecular Mechanisms of Endothelial and Diastolic Dysfunction (Project Heads Kandolf, Reinhard ;  Lang, Florian ;  Tschöpe, Carsten )
• B06 - Parvovirus B19 and Endothelial Regeneration (Project Heads Schmidt-Lucke, Caroline ;  Volk, Hans-Dieter )
• B07 - Cardioprotective and Immunomodulatory Effects of Adiponectin in Inflammatory Cardiomyopathy (Project Heads Scheibenbogen, Carmen ;  Skurk, Carsten )
• B08 - Interaction of Platelets with Progenitor Cells: Implications for the Pathogenesis of Inflammatory Cardiomyopathy (Project Heads Gawaz, Meinrad Paul ;  Stellos, Konstantinos )
• C01 - RNA Interference-Mediated Silencing of Negative SERCA2a Regulators for the Improvement of Ca2+ Homeostasis in DCMi (Project Heads Erdmann, Volker A. ;  Fechner, Henry ;  Vetter, Roland )
• C02 - Characterization of the Inotropic Effects of Cardiotropic Antibodies (Project Heads Felix, Stephan ;  Herda, Lars Roman )
• C03 - Genomwide Analysis of Therapy-Associated Changes in the Gene Expression Program of DCM Patients - Diagnostic Relevance of Expression Signatures (Project Heads Kühl, Uwe ;  Völker, Uwe )
• C04 - Relevance of the Carnitine Transport Proteins OCTN1 and OCTN2 in Inflammatory Cardiomyopathy (Project Heads Grube, Markus ;  Jedlitschky, Gabriele ;  Kroemer, Heyo Klaus )
• C05 - Development of Novel RNA-Based and Gene Therapeutic Strategies in Cardiomyopathies (Project Heads Poller, Wolfgang ;  Scheibenbogen, Carmen )
• C06 - Bedeutung der Pathogenese der Myokarditis und der inflammatorischen Kardiomyopathie für den Einsatz mechanischer Herzunterstützungssysteme (Project Head Hetzer, Roland )
• C07 - Mechanism and Therapeutic Potential of an Accelerated Mitochondrial ADP/ATP-Transport in Inflammatory and Ischemic Cardiomyopathy (Project Head Dörner, Andrea )
• V01 - Central Management (Project Heads Poller, Wolfgang ;  Schultheiss, Heinz-Peter )
• Z01 - Differential Diagnosis and Differential Therapy of Inflammatory Cardiomyopathy (Project Heads Felix, Stephan ;  Kühl, Uwe ;  Schultheiss, Heinz-Peter )
• Z02 - Central Data Management; Biometry and Epidmiology (Project Head Hoffmann, Wolfgang )
• Z03 - Characterization of the Cardiovascular Phenotype and Experimental Therapeutic Approaches in Animal Models (Project Heads Kübler, Wolfgang ;  Riad, Alexander ;  Tschöpe, Carsten )
• Z04 - Phenotypic, Molecular Pathologic, and Immunologic Studies in Mouse Models of Virus-Induced DCMi (Project Head Klingel, Karin )

Applicant Institution shared FU Berlin and HU Berlin through:
Charité - Universitätsmedizin Berlin

Co-Applicant Institution Eberhard Karls Universität Tübingen; Freie Universität Berlin; Humboldt-Universität zu Berlin; Universität Greifswald

Spokesperson Professor Dr. Heinz-Peter Schultheiss