Cadherin/Catenin Function in Arrhythmogenesis

描述(申请人提供)：与结构性心脏病相关的心律失常是美国发病率和死亡率的主要原因。细胞黏附受体中的钙粘附素家族位于黏附连接处，以同质性的方式相互作用，介导强大的细胞-细胞黏附，在维持组织结构中起着关键作用。钙粘附素的黏附强度受连接素的调节，它介导了钙粘附素与肌动蛋白细胞骨架的连接。我们最近开发了心脏限制性N-钙粘素条件性基因敲除小鼠，这种小鼠表现出严重的传导缺陷和心脏性猝死。本研究的长期目标是确定异常的钙粘蛋白/连环蛋白细胞间偶联在致心律失常底物形成中的具体作用，并了解导致缝隙连接重塑的分子机制。为此，我们将利用条件性基因靶向小鼠模型来阐明钙粘附素/连环蛋白复合体在稳定工作心肌缝隙连接中的作用。其具体目的是：1)确定α-连环蛋白在维持心肌细胞间机械和电偶联中的重要性。2)确定N-钙粘附素缺失导致缝隙连接重塑的机制。3)确定N-钙粘蛋白杂合子和N-钙粘蛋白/Cx43复合杂合子是否对应激性心律失常易感。4)确定β-连环蛋白(原球蛋白)在维持缝隙连接稳定性中的作用。患有Naxos病的患者有一种突变的白蛋白，会导致心律失常的右室心肌病。将建立Naxos病的小鼠模型，以研究这些患者心源性猝死的心律失常致病机制。从这些实验中获得的知识将为理解心脏病心律失常的发生机制提供一个分子框架。反过来，我们的研究可能会导致更好的筛查方法来识别因心律失常而有猝死风险的人，并可能产生新的治疗方法。

DESCRIPTION (provided by applicant): Cardiac arrhythmias associated with structural heart disease are a major cause of morbidity and mortality in the United States. The cadherin family of cell adhesion receptors, located in the adherens junction, interacts homophilically to mediate strong cell-cell adhesion and play a key role in the maintenance of tissue structure. The adhesive strength of cadherins is modulated by catenins, which mediate cadherin linkage to the actin cytoskeleton. We recently developed cardiac-restricted N-cadherin conditional knockout mice that exhibit severe conduction defects and sudden cardiac death. The long-term goal of this study is to determine the specific contribution of dysregulated cadherin/catenin intercellular coupling to the formation of the arrhythmogenic substrate and to understand the molecular mechanisms resulting in gap junctional remodeling. Toward this end, we will utilize conditional gene-targeted murine models to elucidate the role of the cadherin/catenin complex in stabilizing gap junctions in the working myocardium. The specific aims are to: 1) Determine the importance of a-catenin in maintaining mechanical and electrical coupling between cardiomyocytes. 2) Determine the mechanism by which loss of N-cadherin leads to remodeling of gap junctions. 3) Determine if N-cadherin heterozygotes and N-cadherin/Cx43 compound heterozygotes are susceptible to stress-induced cardiac arrhythmias. 4) Determine the role of ?- catenin (plakoglobin) in maintaining gap junction stability. Patients suffering from Naxos disease have a mutant form of plakoglobin that causes arrhythmic right ventricular cardiomyopathy. A mouse model of Naxos disease will be generated to investigate the arrhythmogenic mechanism responsible for the sudden cardiac death in these patients. Knowledge gained from these experiments will provide a molecular framework for understanding the mechanism of arrhythmogenesis in heart disease. In turn our studies may lead to better screening methods to identify persons at risk of sudden death due to cardiac arrhythmia, and possibly to novel therapies.