Role of the Raf Kinase Inhibitor Protein in the regulation of the time course of cardiac fibrogenesis

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Pathologic growth of connective tissue is the response to chronic organ damage. Three types of myocardial fibrosis, interstitial, perivascular and reparative fibrosis, play a central role in the cardiac remodeling and are crucial for the morphologic and functional pathogenesis of myocardial hypertrophy, heart failure and atrial fibrillation. However, underlying cellular and molecular mechanisms are not completely understood. Hence, the identification of genetic determinants of fibrogenesis is of importance. To reveal unknown genetic risk factors, a genome-wide screening by Quantitative Trait Loci (QTL) analysis was performed. Our preliminary studies identify Raf Kinase Inhibitor Protein (RKIP, Phosphatidylethanolamine-Binding Protein-I (PEBP-I) as an important genetic risk factor for cardiac fibrogenesis. First experiments confirm the reduction of increased myocardial collagen content induced by aortic ligation and CCl4-treatment in RKIP-knockout mice. The aim of the project is to investigate the role of RKIP-regulated cellular and molecular mechanisms in the time course of cardiac fibrogenesis. Mouse models for three types of cardiac fibrosis, strain-mismatched and strain-matched bone marrow transplantations and expression analysis of cultivated cardiac fibroblasts will be used to identify and to characterize new cellular and molecular starting points for potential preventive interventions.