Molecular Basis of Sudden Cardiac Death

描述（由申请人提供）： 这个持续的计划项目补助金（PPG）申请包括三个项目和两个核心。这些项目的重点是识别引发心律失常和心脏性猝死（SCD）的分子信号。核心假设是细胞内钙（Ca）信号传导的扰动可导致心律失常的触发。我们认为，细胞内钙稳态的扰动，主要是由于有缺陷的调节或功能的离子通道，包括钾，钠，钙通道以及心肌肌浆网上的兰尼定受体/钙释放通道，启动触发致命的心律失常。我们进一步提出，在人类中，肾上腺素能受体的变体形式通过影响细胞内钙信号使个体亚群易患致命性心律失常的风险增加。我们的心脏性猝死的分子基础的理解，由于舒张期泄漏的钙从肌浆网通过心脏ryanodine受体（RyR 2）的重要进展，导致从这个项目。这些进展直接导致了心源性猝死的潜在新疗法（图1）。此外，该项目还有助于发现通过交感神经系统刺激调节IKS钾通道（KCNQ 1/KCNE 1）的新机制。我们发现，这种机制的缺陷是导致患者心脏性猝死的原因。这三个项目的整体联系如下：1）项目1，PI -安德鲁R。Marks，医学博士，哥伦比亚大学生理学和细胞生物物理学主席，哥伦比亚大学分子心脏病学中心主任，有三个目标，重点是肾上腺素能调节对心脏兰尼碱受体/钙释放通道的作用的功能表征。2)项目2，PI - Robert S.卡斯博士，哥伦比亚大学药理学主席，有两个目标，重点是表征钠通道持续活性对钙释放触发的心脏性猝死（SCD）的贡献和SR钙释放对肌膜离子通道的调节; 3）项目3，PI - PI W。J. Lederer，医学博士，哲学博士、马里兰州大学医学生物技术中心主任，有三个目标，重点是确定离子通道突变和肾上腺素能调节对心肌细胞钙信号的影响。建议的两个核心如下：1）行政（A.R.）Marks，PI）; 2）动物模型核心。(J. D 'Armiento，PI -该核心将为四个项目中的每一个项目生成并提供离子通道疾病的遗传动物模型）。

DESCRIPTION (provided by applicant): This continuing Program Project Grant (PPG) application comprises three Projects and two Cores. The focus of the projects is identification of molecular signals that initiate cardiac arrhythmias and sudden cardiac death (SCD). A central hypothesis is that perturbation of intracellular calcium (Ca) signaling can lead to triggers of cardiac arrhythmias. We propose that perturbations of intracellular calcium homeostasis, primarily due to defective regulation or function of ion channels including potassium, sodium, calcium channels as well as the ryanodine receptor/calcium release channel on the cardiac sarcoplasmic reticulum, initiate triggers of fatal cardiac arrhythmias. We further propose that in humans variant forms of adrenergic receptors predispose subsets of individuals to increased risk of fatal cardiac arrhythmias via effects on intracellular calcium signaling. Important advances in our understanding of the molecular basis of sudden cardiac death due to diastolic leak of Ca from the sarcoplasmic reticulum via the cardiac ryanodine receptor (RyR2) have resulted from this project. These advances have lead directly to potential novel therapy for Sudden Cardiac Death (Fig. 1). In addition, this project has contributed to the discovery of a novel mechanism for regulating the IKS potassium channel (KCNQ1/KCNE1) via sympathetic nervous system stimulation. We showed that a defect in this mechanism is responsible for sudden cardiac death in patients. The three projects are integrally linked as follows: 1) Project 1, PI - Andrew R. Marks, M.D., Chair of Physiology and Cellular Biophysics, Columbia University, Director, Center for Molecular Cardiology, Columbia University, has three aims focused on the functional characterization of the effects of adrenergic modulation on the cardiac ryanodine receptor/calcium release channel. 2) Project 2, PI - Robert S. Kass, Ph.D., Chair of Pharmacology, Columbia University, has two aims focused on characterization of contributions of sodium channel sustained activity to calcium release-triggered sudden cardiac death (SCD) and on modulation of sarcolemmal ion channels by SR calcium release; 3) Project 3, PI -- PI W. J. Lederer, M.D., Ph.D., Director Medical Biotechnology Center, University of Maryland, has three aims focused on determining the effects of ion channel mutations and adrenergic modulation on calcium signaling in cardiomyocytes. Two Cores are proposed as follows: 1) Administrative (A.R. Marks, PI); 2) Animal Model Core. (J. D'Armiento, PI - This Core will generate and provide genetic animal models of ion channel diseases to each of the four projects).