Molecular Pathways for Hypertrophy and Cardiomyopathy

描述（由申请人提供）： 心力衰竭中心脏表型的复杂性质表明，不同的途径将负责疾病的发生和进展。近年来，致心律失常性右心室心肌病/发育不良（ARVC/D）和整合素信号级联相关分子异常的基因鉴定引起了我们对细胞-细胞和细胞-细胞外基质复合物在心肌病发展和压力超负荷等应激反应中的作用的关注。这项工作的下一阶段涉及这些分子复合物及其在疾病进展中的作用的严格评估，将它们与完整心脏，离体心脏和离体肌细胞中的特定心脏收缩，电生理和机械特性联系起来。这也将使我们能够探索这些通路与其他已知或新的通路之间的潜在联系，这些通路在人类或其他实验系统中被发现。因此，该计划的中心目标是确定心肌细胞关键粘附连接中的分子复合物如何触发或促成心脏肥大、心肌病和向心力衰竭转变的发病机制。该提案的总体假设是，心脏细胞-细胞和细胞-细胞外基质分子复合物的缺陷可通过破坏机电功能、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。 在当前的项目资助申请中，我们将主要关注闰盘中参与桥粒形成的蛋白质子集（斑珠蛋白）;以及那些是粘连筋膜连接的一部分的蛋白质（柯萨奇病毒和腺病毒受体（CAR），闭合小带-1（ZO-1），斑珠蛋白和黏着斑蛋白/偏黏着斑蛋白）。此外，我们将交互式地址costameric分子的整合素复合物（黏着斑蛋白，metavinculin，talin和PINCH）的肌膜的细胞质侧。

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).