Molecular Pathways for Hypertrophy and Cardiomyopathy

描述(由申请人提供)： 心力衰竭心脏表型的复杂性表明，不同的途径将导致疾病的发生和发展。近年来，随着对致心律失常性右室心肌病/发育不良(ARVC/D)相关基因和整合素信号级联相关分子异常的发现，细胞-细胞和细胞-细胞外基质复合体在心肌病的发生和对压力超负荷等应激反应中的作用引起了人们的关注。这项工作的下一阶段涉及对这些分子复合体及其在疾病进展中的作用的严格评估，将它们与完整心脏、分离心脏和分离心肌细胞的特定心脏收缩、电生理和机械特性联系起来。这也将使我们能够探索这些途径与其他已知或新途径之间的潜在联系，这些途径是在人类或其他实验系统中发现的。因此，该计划的中心目标是确定心肌细胞关键粘连连接中的分子复合体如何触发或促进心肌肥厚、心肌病和向心力衰竭的过渡。该提案的总体假设是，心肌细胞-细胞和细胞-细胞外基质分子复合体的缺陷可通过扰乱机电功能、结构完整性或信号转导而导致不同形式的肥大、心肌病和心律失常。 在当前的计划项目拨款申请中，我们将主要关注间盘中参与桥粒形成的蛋白质子集(斑点红蛋白)；以及属于筋膜粘连连接部分的蛋白质子集(柯萨奇病毒和腺病毒受体(CAR)、透明带封闭蛋白-1(ZO-1)、斑点球蛋白和纽蛋白/Metavinculin)。此外，我们还将交互处理整合素复合体中肌膜细胞质一侧的胞核分子(纽蛋白、异长春花素、Talin和Pinch)。

DESCRIPTION (provided by applicant): The complex nature of the cardiac phenotype in heart failure suggests that diverse pathways will be responsible for disease initiation and progression. Recently, the identification of genes that are responsible for Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (ARVC/D) and abnormalities in molecules related to the integrin signaling cascade has drawn our attention to the role that the cell-cell and cell-extracellular matrix complexes have in the development of cardiomyopathy and the response to stresses such as pressure overload. The next stage of this work involves the rigorous evaluation of these molecular complexes and their role in disease progression, linking them to specific cardiac contractile, electrophysiological, and mechanical properties in both the intact heart, the isolated heart and the isolated myocyte. This will also allow us to explore potential connections between these pathways and other known or novel pathways that are uncovered in either human or other experimental systems. Accordingly, the central objective of this program is to identify how molecular complexes in the key adhesive junctions of the cardiac myocyte trigger or contribute to the pathogenesis of cardiac hypertrophy, cardiomyopathy, and the transition to heart failure. The overall hypothesis of the proposal is that defects in the cardiac cell-cell and cell-extracellular matrix molecular complexes can lead to distinct forms of hypertrophy, cardiomyopathy and arrhythmia by disrupting electromechanical function, structural integrity or signal transduction. In the current program project grant application we will focus primarily on a subset of proteins in the intercalated disc that are involved in formation of the desmosomes (plakoglobin); and those which are part of the fascia adherens junction (coxsackievirus and adenovirus receptor (CAR), zonula occludins-1 (ZO-1), plakoglobin and vinculin/ metavinculin). In addition, we will interactively address costameric molecules on the cytoplasmic side of the sarcolemma in the integrin complex (vinculin, metavinculin, talin and PINCH).