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：
7568905
负责人：
GLENN Lawrence RADICE
金额：
$ 38.63万
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/7568905
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不齐是美国发病率和死亡率的主要原因。位于粘附连接中的细胞粘附受体的钙粘蛋白家族均具有同质性相互作用，以介导强细胞粘附并在维持组织结构中起关键作用。钙粘着蛋白的粘附力是由蛋白茶碱调节的，catenin介导了钙粘着蛋白与肌动蛋白细胞骨架。我们最近开发了心脏限制的N-钙粘蛋白有条件敲除小鼠，表现出严重的传导缺陷和猝死。这项研究的长期目标是确定失调的钙粘着蛋白/catenin间偶联对心律失常基底物形成的特定贡献，并了解导致间隙连接性重塑的分子机制。为此，我们将利用条件基因靶向的鼠模型来阐明钙粘蛋白/catenin络合物在稳定工作心肌中的间隙连接方面的作用。具体目的是：1）确定a-catenin在维持心肌细胞之间的机械和电耦合方面的重要性。 2）确定N-钙粘蛋白损失导致间隙连接重塑的机制。 3）确定N-钙粘着蛋白杂合子和N-钙粘蛋白/CX43化合物杂合子是否易受压力诱导的心律不齐。 4）确定？ - catenin（plakoglobin）在保持间隙连接稳定性中的作用。患有NAXOS疾病的患者具有一种突变形式的斑lakoglobin，会导致心律不齐的右心肌病。将生成一种纳克斯疾病的小鼠模型，以研究导致这些患者突然心脏死亡的心律失常机制。从这些实验中获得的知识将提供一个分子框架，以了解心脏病中心律失常发生的机制。反过来，我们的研究可能会导致更好的筛查方法，以识别因心律不齐而导致猝死风险的人，甚至可能是新疗法。