Molecular Basis of Cardiac Arrhythmia and Sudden Death

心律失常和猝死的分子基础

• 批准号: 6927656
• 负责人: SUI RONG WAYNE CHEN
• 金额: $ 21.6万
• 依托单位: UNIVERSITY OF CALGARY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6927656
• 关键词: antiarrhythmic agent; arrhythmia; arrhythmic agent; calcium channel; cardiovascular pharmacology; gene mutation; genetic polymorphism; molecular /cellular imaging; molecular pathology; protein structure function; radiotracer; receptor expression; single cell analysis; site directed mutagenesis; sudden cardiac death

DESCRIPTION (provided by applicant): Cardiac arrhythmia is the leading cause of sudden death, particularly, for patients with heart failure. Disappointingly, most current treatments have little or no survival benefits and new therapies are urgently needed. The cardiac calcium release channel (ryanodine receptor type 2, RyR2) is quickly emerging as an important point in the pathogenesis of cardiac arrhythmia. Mutations in RyR2 have been linked to at least 2 forms of cardiac arrhythmias, catecholaminergic polymorphic ventricular tachycardia (CPVT) and arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Defective RyR2 channel function has also been implicated in drug-induced cardiac arrhythmia. Our goal is to define the actions of disease-causing RyR2 mutations and of RyR2-interacting pro- and anti-arrhythmic agents, and the molecular mechanism of channel function that mediates their actions, thereby providing the knowledge basis necessary for the development of effective anti-arrhythmic therapies. 3 specific aims are proposed. 1. Define the functional consequences of CPVT RyR2 mutations. The functional impacts of CPVT mutations on RyR2 channel function will be investigated at the whole cell, molecular and single channel levels. 2. Understand the molecular actions of RyR2-interacting pro- and anti-arrhythmic agents. The impacts of RyR2-interacting pro- and anti-arrhythmic agents on RyR2 channel function will be assessed by a combination of techniques including single cell calcium imaging, single channel analysis and radioligand binding. 3. Define the molecular basis of calcium regulation of the RyR2 channel. Site-directed mutagenesis in conjunction with single channel analysis will be employed to systematically define the role of the channel pore region in calcium activation of the RyR2 channel. These studies will shed novel and important insight into the causal mechanisms of RyR2-associated cardiac arrhythmias and sudden death, and will have profound implications to the treatment of cardiac arrhythmias arising from various cardiac diseases including heart failure.

描述（申请人提供）：心律失常是猝死的主要原因，尤其是对于心力衰竭患者。令人遗憾的是，目前大多数治疗方法几乎没有生存益处，迫切需要新的治疗方法。心脏钙释放通道（Ryanodine receptor type 2，RyR2）是心律失常发病机制中的一个重要环节。RyR2的突变与至少2种心律失常有关，即儿茶酚胺能多态性室性心动过速（CPVT）和致心律失常性右心室心肌病2型（ARVD 2）。RyR2通道功能缺陷也与药物诱导的心律失常有关。我们的目标是定义致病RyR2突变和RyR2相互作用的促和抗血小板生成剂的作用，以及介导其作用的通道功能的分子机制，从而为开发有效的抗血小板生成疗法提供必要的知识基础。提出了三个具体目标。1.定义CPVT RyR2突变的功能后果。将在全细胞、分子和单通道水平上研究CPVT突变对RyR 2通道功能的功能影响。2.了解RyR2相互作用的促和抗肿瘤剂的分子作用。将通过包括单细胞钙成像、单通道分析和放射性配体结合在内的技术组合来评估RyR2相互作用的促和抗血小板生成剂对RyR2通道功能的影响。3.定义钙调节RyR2通道的分子基础。将采用定点诱变结合单通道分析来系统地确定通道孔区域在RyR2通道的钙激活中的作用。这些研究将为RyR2相关心律失常和猝死的因果机制提供新的重要见解，并将对各种心脏疾病（包括心力衰竭）引起的心律失常的治疗产生深远的影响。