Molecular Basis of Cardiac Arrhythmia and Sudden Death

描述（由申请人提供）：心律失常是猝死的主要原因，尤其是心力衰竭患者。令人失望的是，大多数目前的治疗方法对生存的好处很少或没有，迫切需要新的治疗方法。心脏钙释放通道（ryyanodine受体2型，RyR2）在心律失常的发病机制中迅速成为一个重要的点。RyR2突变与至少两种形式的心律失常有关，儿茶酚胺能多形性室性心动过速（CPVT）和致心律失常的2型右室心肌病（ARVD2）。RyR2通道功能缺陷也与药物性心律失常有关。我们的目标是明确致病的RyR2突变和RyR2相互作用的促和抗心律失常药物的作用，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心律失常疗法提供必要的知识基础。提出了3个具体目标。1. 定义CPVT RyR2突变的功能后果。CPVT突变对RyR2通道功能的功能影响将在全细胞、分子和单通道水平上进行研究。2. 了解ryr2相互作用的促和抗心律失常药物的分子作用。通过单细胞钙成像、单通道分析和放射性配体结合等技术组合评估RyR2相互作用的促和抗心律失常药物对RyR2通道功能的影响。3. 明确RyR2通道钙调控的分子基础。位点定向诱变结合单通道分析将被用于系统地定义通道孔区域在RyR2通道钙活化中的作用。这些研究将为ryr2相关的心律失常和猝死的因果机制提供新的和重要的见解，并将对包括心力衰竭在内的各种心脏疾病引起的心律失常的治疗产生深远的影响。

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.