Cadherin/Catenin Function in Arrhythmogenesis

描述（由申请人提供）：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。细胞黏附受体钙粘蛋白家族位于黏附体连接处，通过同源相互作用介导强细胞-细胞黏附，在组织结构的维持中发挥关键作用。钙粘蛋白的粘附强度由钙粘蛋白调节，钙粘蛋白介导钙粘蛋白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 -钙粘蛋白条件敲除小鼠，这些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失调的钙粘蛋白/连环蛋白细胞间偶联对心律失常底物形成的具体贡献，并了解导致间隙连接重构的分子机制。为此，我们将利用条件基因靶向小鼠模型来阐明钙粘蛋白/连环蛋白复合物在稳定工作心肌间隙连接中的作用。具体目的是：1)确定a-catenin在维持心肌细胞间机械和电耦合中的重要性。2)确定n -钙粘蛋白缺失导致缝隙连接重构的机制。3)确定N-cadherin杂合子和N-cadherin/Cx43复合杂合子是否易发生应激性心律失常。4)确定？-连环蛋白（血小板红蛋白）在维持间隙连接稳定性中的作用。患有纳克索斯病的患者有一种突变形式的血小板红蛋白，会导致心律失常的右心室心肌病。本研究将建立纳克索斯病小鼠模型，探讨导致这些患者心源性猝死的心律失常发生机制。从这些实验中获得的知识将为理解心脏病中心律失常发生的机制提供一个分子框架。反过来，我们的研究可能会带来更好的筛查方法，以识别因心律失常而猝死的风险人群，并可能带来新的治疗方法。

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.