Molecular Basis of Sudden Cardiac Death

这项关于心源性猝死项目赠款(PPG)的提案旨在通过将遗传学与分子和细胞生物学以及生物物理学相结合来加强我们对SCD的理解。这项拟议研究的总体目标是确定引发致命性心律失常的细胞和分子触发因素。对正常和病理性心肌细胞电兴奋性的分子基础的新认识将是结合非侵入性检测的基因-表型相关性的基础，这一基本前提将是将基因-表型相关性与非侵入性检测相结合用于患者风险分层的基础。主要目标：1)阐明导致SCD的致命性心律失常的触发因素的分子基础；2)建立基因-表型相关性，可用于识别可能接受更积极治疗的心脏性猝死的高危个体。这种方法的基本原理是，了解心脏性猝死诱因的分子基础将为风险分层提供机制基础，并可能导致新的治疗方法。提出了四个项目和两个核心(管理、鼠标模型)。项目1将确定变异的β-肾上腺素能受体(BetaAR)和兰尼定受体(RyR)与心源性猝死风险增加相关。项目2将研究肾上腺素能调节RyR/细胞内钙释放通道在启动胎儿钙依赖型心律失常触发中的作用。项目3将使用已识别的人类心脏离子通道和/或与长Q-T综合征和Brugada综合征相关的信号分子突变作为范例，测试离子通道活动的变化可能改变细胞动作电位的配置的假设，这有助于钙稳态的变化，进而触发心律失常活动。项目4将调查局部和整体钙信号的扰动在启动致命性心律失常的触发因素中的作用。需要检验的假设是，离子通道和肾上腺素能信号传导的扰动改变了心肌细胞的钙稳态，触发了致命性心脏介导的信号传导，改变了心肌细胞的钙稳态，引发了致命性心律失常。所有四个项目的一个主要焦点是确定引发心律失常事件的触发因素。因此，这项工作有可能确定心源性猝死的机制基础。

This proposal for a Program Project Grant (PPG) in Sudden Cardiac Death is designed to enhance our understanding of SCD by combining genetics with molecular and cellular biology and biophysics. The overall goal of the proposed research is to identify the cellular and molecular triggers that initiate fatal cardiac arrhythmias. A fundamental premise that new understandings regarding the molecular basis of normal and pathological cardiomyocyte electrical excitability will be the foundations upon which genotype-phenotype correlates combined with non-invasive testing will the foundations upon which genotype-phenotype correlations combined with non-invasive testing will be used to risk stratify patients. Major goals: 1) to elucidate the molecular basis of the triggers that initiate fatal cardiac arrhythmias that cause SCD; and 2) to establish a genotype-phenotype correlations that can be used to identify individuals at high risk for Sudden Cardiac Death who may be candidates for more aggressive therapy. The rationale for this approach is that understanding the molecular basis of the triggers for Sudden Cardiac Death will provide a mechanistic basis for risk stratification and may lead to novel therapeutic approaches. Four projects and two cores (administrative, mouse models) are proposed. Project 1 will identify variant beta- adrenergic receptors (betaAR) and ryanodine receptors (RyR) associated with increase risk of Sudden Cardiac Death. Project 2 will examine the role of adrenergic modulation of RyR/intracellular calcium release channels in initiating triggers of fetal calcium-dependent cardiac arrhythmias. Project 3 will use identified human mutations of cardiac ion channels and/or signaling molecules linked to the Long Q-T Syndrome and Brugada Syndrome as Paradigms to test the hypothesis that changes in ion channel activity may alter the configuration of the cellular action potential which contributes to changes in calcium homeostasis that, in turn, triggers arrhythmic activity. Project 4 will investigate the role of perturbations of local and global calcium signaling in initiating triggers of fatal cardiac arrhythmias. The hypothesis to be tested is that perturbations of ion channel and adrenergic mediated signaling alter calcium homeostasis in cardiomyocytes, generating triggers for fatal cardiac mediated signaling alter calcium homeostasis in cardiomyocytes, generating triggers for fatal cardiac arrhythmias. A major focus of all four projects is identification of triggers that initiate arrhythmic events. Thus, this work has the potential to determine a mechanistic basis for Sudden Cardiac Death.