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TRR 19:  Inflammatory Cardiomyopathy - Molecular Pathogenesis and Therapy

Subject Area Medicine
Biology
Term from 2004 to 2013
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 5486135
 
Final Report Year 2014

Final Report Abstract

Clinical And Socioeconomic Background: CRC Transregio 19 (CRC/TR 19) was supported 01.07.2004 to 31.12.2013. Goals of this CRC “Inflammatory Cardiomyopathy – Molecular Pathogenesis and Treatment” were elucidation of structural and epidemiological foundations, and improvement of differential diagnosis, treatment, and long-term prognosis of inflammatory cardiomyopathy (DCMi), a subtype of dilated cardiomyopathy. Besides coronary heart disease, DCM is the most frequent cause of heart failure. Among ≈1.5 million heart failure patients in Germany alone, ≈500.000 patients develop heart failure on basis of DCM which has the highest incidence from 3rd-5th decade of life. Despite progress in conventional heart failure therapy, prognosis of this disease remains severe with 5-years mortality of ≈50%. Direct economical burden is estimated at 2-4 billion € per year, enhanced by the fact that patients are usually young at 10-30 years before retirement age. Additional costs arise from heart transplantation or cardiac assist device therapy for patients with terminal heart failure. Important research achievements of CRC/TR 19 over all funding periods encompass the following: Structural Foundations and Epidemiology of the Disease: Structural foundations at the molecular and cellular level, and epidemiology of DCMi including exogenous and genetic contributing factors: Regarding structural foundations, CRC identified multiple new regulators of innate and adaptive immunity, both proteins and ncRNA (e.g. PARs, CCNs, APN, miRs, lncRNAs), and investigated their roles in the pathogenesis of viral and autoimmune DCMi. Molecular and cell structures determining cardiotropic virus infections were investigated in depth, including expression patterns and biological functions of cellular receptors for viruses (e.g. for CVB3, B19V) and cell-specific properties enabling replicative vs. latent virus infections. Knockout and transgenic animal and cell culture models were used to elucidate determinants of the differential cellular and organ tropism, and intracellular behavior, of viruses relevant in the context of DCMi. Regarding epidemiology, the frequency of multiple cardiotropic viruses (e.g. CVB3, ADV, B19V, HHV6) and disease associations were determined in large cohorts. Further, mutations in immune response genes were identified (e.g. TLRs). Novel Molecular Pathomechanisms and Therapeutic Strategies: Virus-host interactions were investigated under the aspects of 1. molecular virology and direct virus effects and 2. immune-system mediated indirect effects. Regarding aspect 1, activation/silencing mechanisms of viruses in different target cells were characterized in models and patients, including the characterization of protein-coding and noncoding virus-derived transcripts. This enabled e.g. the discrimination of B19V-positive patient subgroups distinguished by viral transcriptional activity, and similar studies on other cardiotropic viruses are under way. Regarding aspect 2, overwhelming impact of indirect immunological vs. direct virological damage under certain conditions became evident from work in immunogenetically modified animal models (e.g. TRIF, TLR, PAR, APN, lncRNA knockout mice), and some of these finding were already confirmed in patients. Of note, disturbed immune cell migration emerged as a unifying theme mediating the influence of immunogenetic factors/deficiencies upon cardiac pathogenesis. Accordingly, immune system-heart interactions became a central research and will certainly influence research in the field beyond the CRC. CRC research on aspects 1 and 2 led to important new insights and the identification of novel targets (proteins, miRs, lncRNAs) for treatment of dysregulated pathogenic immune system functions. Regarding direct antiviral therapies, e.g. recombinant protein-based blockade or RNAi-mediated silencing of virus receptors were evaluated, and RNAi to silence pathogenic virus-encoded transcripts. Regarding immunomodulation therapies, e.g. new cell migration-modulating proteins and mimetic peptides were discovered and evaluated, as well as anti-miR oligonucleotides and mesenchymal stem cells to control immune systemheart interactions. Novel delivery systems for in vivo application of molecular therapeutic tools were newly developed by the CRC. Clinical Diagnostic and Therapeutic Translation of New Insights: During the decade of funding, a very large clinical data set and biosamples collection accumulated and enabled diagnostic translational research 1. on long-term natural disease courses associated with DCMi subtypes (different cardiotropic viruses, various forms of pathogenic immune reactions) and 2. to identify novel markers for their prognostic assessment. The CRC network has created the data and biosample basis to enable such studies, and employed it to identify clinical, protein, and ncRNA prognostic markers of disease course. Without the continuous interdisciplinary cooperation between clinical and basic research disciplines within the CRC network over many years, these translational studies would certainly have been impossible. In parallel with these investigations, and supporting them from the clinical side, novel diagnostic procedures and guidelines for clinical practice were written by or with CRC reseachers. In this way, the clinical differential diagnostics, prognostic assessment of DCMi has been greatly improved, which in turn is a prerequisite for more targeted and efficient differential therapies of the various subtypes. Implications of CRC for Future Research: CRC research as outlined above has important implications beyond the primary target disease DCMi, since several research pathways have led to new pathogenic processes and therapeutic strategies of high interest for cardiovascular medicine in general. One of these is the continued exploration of immune system-heart interactions, which play key roles in multiple cardiovascular disease associated with pathogenic immune processes. A second pathway has led, triggered by both clinical and experimental observations, to increasing awareness of the pathogenic and therapeutic implications of the noncoding human genome, including miRs and lncRNAs as pathogenic factors and possible therapeutic targets. Both of these lines of CRC work converge with important research from other research groups worldwide, documenting impact and role of CRC research in the current international context. This includes also international efforts for clinical translation of targeted molecular approaches, e.g. gene and other nucleic acid-based therapies and recombinant immune-modulating proteins, peptides, and small molecule drugs. International cooperation towards these goals will be continued in years to come.

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