Molecular Basis of Sudden Cardiac Death

这项持续计划项目赠款(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。一个中心假设是，细胞内钙信号的扰动可能导致心律失常的触发。我们认为，细胞内钙稳态的紊乱，主要是由于钾、钠、钙通道以及心肌肌浆网上兰尼定受体/钙释放通道等离子通道的调节或功能缺陷，启动了致命性心律失常的触发。我们进一步提出，在人类中，不同形式的肾上腺素能受体通过对细胞内钙信号的影响，使个体亚群易患致命性心律失常的风险增加。该项目在了解舒张期通过心脏兰尼定受体(RyR2)从肌浆网漏出的钙离子导致心源性猝死的分子基础方面取得了重要进展。这些进展直接导致了潜在的治疗心脏性猝死的新方法(图1)。此外，该项目还有助于发现一种通过刺激交感神经系统来调节IKS钾通道(KCNQ1/KCNE1)的新机制。我们证明，这一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，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Pi-Andrew R.Marks，医学博士，专注于肾上腺素能调节对心脏兰尼定受体/钙释放通道的影响的功能表征。2)项目2，哥伦比亚大学药理学主任Pi-Robert S.Kass，Ph.D.，项目2的两个目标是确定钠通道持续活动对钙释放引发的心脏性猝死(SCD)的贡献，以及SR钙释放对肌膜离子通道的调节；3)项目3，PI--马里兰大学医学生物技术中心主任Pi W.J.Leder，医学博士，博士，三个目标侧重于确定离子通道突变和肾上腺素能调制对心肌细胞钙信号的影响。提出了两个核心：1)管理(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个项目生成并提供离子通道疾病的遗传动物模型)。

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).