Calcium Triggered Arrhythmias and Sudden Cardiac Arrest

钙引发的心律失常和心脏骤停

• 批准号: 8100423
• 负责人: Richard L Moss
• 金额: $ 193.87万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8100423
• 关键词: Calcium; Triggered; Arrhythmias; Sudden; Cardiac

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.

该研究项目旨在满足进一步了解 CPVT、LQTS 和 HCM 等遗传性疾病和综合征中 Ca2+ 引发心律失常的遗传基础和电生理机制的迫切需要，从而更好地了解心脏骤停的发病机制在这些人群中。具体目标是确定 (1) 心律失常易感性增加的遗传基础，包括离子通道、细胞内 Ca2+ 释放通道和相关蛋白的突变或多态性所起的致病和调节作用，(2) 心律失常的电生理学基础触发由离子通道、Ca 释放通道或小鼠模型中表达的肌原纤维蛋白的多种突变引起的心律失常，以及 (3) 是否触发由不同原发原因引起的心律失常最终涉及共同的细胞机制，该机制导致细胞中异常的电活动和心脏骤停。该计划由四个子项目和四个核心组成。子项目 1 将确定新型 RYR2 突变的功能后果，包括 RyR2 中常见的多态性，以及分子表型导致 CPVT 临床表型的机制。子项目 2 将研究 CPVT 中 KCNJ2 突变的新观察结果，并确定这些突变目前导致 CPVT 的机制。子项目3将使用HCM的敲入模型来确定Ca2+触发心律失常的机制以及该疾病中心律失常风险的决定因素。子项目 4 将在已知基因以及 CPVT 和一组 HC 患者中寻找新的候选基因，以测试与 CPVT 相关的基因的功能多态性可能使一些 HCM 患者容易引发心律失常的想法。科学核心侧重于（核心 B）表现出心脏骤停和/或肥厚性心肌病的患者群体的基因分型，（核心 C）分子生物学和心脏病动物模型的开发，以及（核心 D）小鼠品系的体内功能表征在子项目中开发。核心将为子项目提供支持，并促进新研究方向的发展。我们独特的互补方法将产生有关遗传和亚细胞过程的新信息，这些信息会增加人类遗传性心脏病中心脏骤停的风险。