Calcium Triggered Arrhythmias and Sudden Cardiac Arrest

这项研究计划旨在解决更好地了解遗传性疾病和综合征(如CPVT、LQTS和HCM)中钙离子触发的心律失常的遗传基础和电生理机制的迫切需要，以此作为更好地了解这些人群心脏骤停的发病机制的手段。具体目标是确定(1)触发心律失常易感性增加的遗传基础，包括离子通道、细胞内钙释放通道和相关蛋白质的突变或多态性所起的致病和调节作用，(2)由离子通道、钙释放通道或在小鼠模型中表达的肌纤维蛋白的各种突变引起的触发心律失常的电生理学基础，以及(3)由不同原发原因引起的触发心律失常是否最终涉及导致细胞异常电活动和心脏骤停的共同细胞机制。该计划由四个子项目和四个核心组成。子项目1将确定新的RYR2突变的功能后果，包括RyR2中的一个常见多态，以及该分子表型导致CPVT临床表型的机制。子项目2将调查对CPVT中KCNJ2突变的新观察，并确定这些突变目前导致CPVT的机制。子项目3将使用HCM的敲打模型来确定钙离子触发的心律失常的机制和这种疾病中心律失常的风险决定因素。子项目4将在已知基因中寻找新的突变，以及CPVT的新候选基因，并在一组HC患者中进行研究，以测试与CPVT相关的基因的功能多态可能使一些HCM患者易患触发心律失常的想法。科学核心集中在(核心B)表现为心脏骤停和/或肥厚性心肌病的患者队列的基因分型，(核心C)分子生物学和心脏病动物模型的发展，以及(核心D)在子项目中开发的小鼠品系的体内功能特征。这些核心将为次级项目提供支持，并将促进发展新的研究方向。我们独特的互补方法将产生关于遗传和亚细胞过程的新信息，这些过程增加了人类遗传性心脏病心脏骤停的风险。

This program of research is designed to address the critical need for greater understanding of the genetic basis and electrophysiological mechanisms of Ca2+ triggered arrhythmias in inherited diseases and syndromes such as CPVT, LQTS, and HCM as a means to better understand the pathogenesis of sudden cardiac arrest in these populations. Specific objectives are to determine (1) the genetic basis for increased susceptibility to triggered arrhythmias, including the causative and modifier roles played by mutations or polymorphisms in ion channels, the intracellular Ca2+ release channel, and associated proteins, (2) the electrophysiological basis for triggered arrhythmias arising from a diverse range of mutations in ion channels, the Ca release channel, or myofibrillar proteins expressed in murine models, and (3) whether triggered arrhythmias arising from different primary causes ultimately involve a common cellular mechanism that gives rise to aberrant electrical activity in the cell and sudden cardiac arrest. The program is comprised of four sub-projects and four cores. Subproject 1 will determine the functional consequences of novel RYR2 mutations, including a common polymorphism in RyR2, and the mechanisms by which the molecular phenotype causes the clinical phenotype of CPVT. Subproject 2 will investigate the novel observation of KCNJ2 mutations in CPVT and determine the mechanisms by which these mutations current cause CPVT. Subproject 3 will use knock-in models of HCM to determine the mechanisms for Ca2+-triggered arrhythmia and determinants of risk for arrhythmias in this disease. Subproject 4 will pursue novel mutations in known genes, as well as novel gene candidates for CPVT and also in a cohort of HC patients, to test the idea that functional polymorphisms in genes related to CPVT may predispose some HCM patients to triggered arrhythmias. Scientific cores are focused on (Core B) genotyping of patient cohorts exhibiting sudden cardiac arrest and/or hypertrophic cardiomyopathy, (Core C) molecular biology and development of animal models of cardiac disease, and (Core D) in vivo functional characterization of mouse lines developed in the subprojects. The cores will provide support to the sub-projects and will facilitate development of new research directions. Our uniquely complementary approaches will yield new information concerning genetic and sub-cellular processes that confer increased risk for sudden cardiac arrest in heritable cardiac diseases in humans.