Calcium Triggered Arrhythmias and Sudden Cardiac Arrest

钙引发的心律失常和心脏骤停

基本信息

批准号：
8509771
负责人：
Richard L Moss
金额：
$ 190.51万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2015-06-30
项目状态：
已结题

项目摘要

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.

该研究计划旨在解决对遗传性疾病和综合症（例如CPVT，LQTS和HCM）中Ca2+触发心律不齐的遗传基础和电生理机制的关键需求，以便更好地了解这些人群中突然心脏抑制的病原体。具体目标是确定（1）增加对心律不齐的易感性的遗传基础，包括因离子通道中突变或多态性在离子通道中扮演的病变和修饰的作用，细胞内Ca2+释放通道和相关蛋白的遗传学作用，以及相关的蛋白质，（2）与触发的Arlythmias的电流范围，或者是触发的Arythmias或多样性范围的范围。在鼠模型中表达的肌原纤维蛋白以及（3）是否触发了由不同的原发性原因引起的心律不齐，最终涉及一种常见的细胞机制，导致细胞中的电活动异常和心脏骤停。该程序由四个子项目和四个内核组成。 subproject 1将确定新型RYR2突变的功能后果，包括RYR2中的常见多态性，以及分子表型引起CPVT临床表型的机制。 subproject 2将研究CPVT中KCNJ2突变的新观察结果，并确定这些突变导致CPVT的机制。第3次副本将使用HCM的敲入模型来确定该疾病中心律失常风险的CA2+触发心律不齐的机制。 subproject 4将在已知基因以及CPVT和HC患者队列中进行新的突变，以测试与CPVT基因中的功能多态性有关的想法，可能使某些HCM患者倾向于触发心律失常。科学核心的重点是（核心）（核心）的基因分型，表现出心脏骤停和/或肥厚性心肌病（Core C）分子生物学和心脏疾病动物模型的发展，以及（核心D）在supproxprojjects中开发的小鼠线的体内功能表征。核心将为下项目提供支持，并有助于开发新的研究方向。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，从而赋予人类遗传性心脏病突然心脏骤停的风险增加。