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

结缔组织的病理性生长是对慢性器官损伤的反应。间质性、血管周围和修复性心肌纤维化在心脏重构中起着核心作用，在心肌肥厚、心力衰竭和心房颤动的形态和功能发病机制中起着至关重要的作用。然而，潜在的细胞和分子机制并不完全清楚。因此，确定肝纤维化的遗传决定因素具有重要意义。为了揭示未知的遗传危险因素，采用数量性状基因座(QTL)分析进行全基因组筛查。我们的初步研究证实Raf Kinase Inhibitor Protein(RKIP，磷脂酰乙醇胺结合蛋白-I，PEBP-I)是心脏纤维化的重要遗传危险因素。首次实验证实，在RKIP基因敲除小鼠中，主动脉结扎和CCl4治疗可减少增加的心肌胶原含量。该项目的目的是研究RKIP调控的细胞和分子机制在心脏纤维化形成时间过程中的作用。三种类型的心脏纤维化的小鼠模型、品系不匹配和品系匹配的骨髓移植以及培养的心脏成纤维细胞的表达分析将被用于识别和表征潜在预防干预的新的细胞和分子起点。

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.