Cadherin/Catenin Function in Arrhythmogenesis

钙粘蛋白/连环蛋白在心律失常发生中的功能

基本信息

批准号：
7356008
负责人：
GLENN Lawrence RADICE
金额：
$ 38.68万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-15 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7356008
关键词：
A Mouse Actins Adherens Junction Adhesives Alleles Animals Anti-Arrhythmia Agents Arrhythmia Arrhythmogenic Right Ventricular Dysplasia Binding Cadherins Cardiac Cardiac Myocytes Cardiomyopathies Cell Adhesion Cell membrane Cell-Cell Adhesion Complex Connexin 43 Coupling Cytoskeleton Defect Development Dilated Cardiomyopathy Disease Exhibits Family Gap Junctions Gene Targeting Genes Genetic Goals Heart Diseases Herpes zoster disease Heterozygote Hypertrophy Incidence Intercalated disc Ischemia Knock-out Knockout Mice Knowledge Lead Longevity Maintenance Mechanics Mediating Methods Modeling Molecular Molecular Target Morbidity - disease rate Mus Muscle Cells Mutation Myocardium N-Cadherin Pathway interactions Patients Persons Phenotype Play Property Research Research Personnel Risk Role Screening procedure Stress Structure Sudden Death Testing Tissues United States Ventricular Work adhesion receptor design insight loss of function mortality mouse model mutant novel plakoglobin research study sudden cardiac death

项目摘要

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.

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和死亡的主要原因。细胞粘附受体的钙粘蛋白家族位于粘附连接处，通过同质相互作用介导强的细胞间粘附，并在维持组织结构中发挥关键作用。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-钙粘蛋白条件敲除小鼠，其表现出严重的传导缺陷和心源性猝死。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心律失常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。具体目标是： 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-钙粘蛋白的丢失导致间隙连接重塑的机制。 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诱发的心律失常敏感。 4) 确定β-连环蛋白（斑珠蛋白）在维持间隙连接稳定性中的作用。患有纳克索斯病的患者具有斑珠蛋白突变形式，可导致心律失常性右心室心肌病。将建立纳克索斯病小鼠模型来研究导致这些患者心源性猝死的心律失常机制。从这些实验中获得的知识将为理解心脏病心律失常发生机制提供分子框架。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面临猝死风险的人，并可能带来新的治疗方法。