Cadherin/Catenin Function in Arrhythmogenesis

描述（由申请人提供）：在美国，与结构性心脏病相关的心律失常是发病率和死亡率的主要原因。钙粘蛋白家族的细胞粘附受体位于粘附连接处，以亲嗜性相互作用来介导强的细胞-细胞粘附，并且在组织结构的维持中起关键作用。钙粘蛋白的粘附强度由连环蛋白调节，连环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-钙粘蛋白条件性敲除小鼠，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钙粘蛋白/连环蛋白细胞间偶联失调对致炎底物形成的具体贡献，并了解导致间隙连接重塑的分子机制。为此，我们将利用有条件的基因靶向小鼠模型来阐明钙粘蛋白/连环蛋白复合体在稳定工作心肌间隙连接中的作用。具体目的是：1）确定α-连环蛋白在维持心肌细胞之间的机械和电耦合中的重要性。2)确定N-钙粘蛋白丢失导致间隙连接重塑的机制。3)确定N-cadherin杂合子和N-cadherin/Cx43复合杂合子是否易受应激诱导的心律失常的影响。4)确定的作用？-连环蛋白（斑珠蛋白）维持间隙连接稳定性。患有纳克索斯病的患者有一种突变形式的斑珠蛋白，可导致心肌梗塞性右心室心肌病。将产生Naxos病的小鼠模型以研究导致这些患者心源性猝死的致瘤机制。从这些实验中获得的知识将为理解心脏病中血管生成的机制提供分子框架。反过来，我们的研究可能会导致更好的筛查方法，以确定由于心律失常而猝死的风险，并可能导致新的治疗方法。

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.