Molecular Basis of Sudden Cardiac Death

这项心脏性猝死项目资助（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增强我们对SCD的理解。这项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。一个基本前提是，关于正常和病理性心肌细胞电兴奋性的分子基础的新理解将是基因型-表型相关性与非侵入性检测相结合的基础，将是基因型-表型相关性与非侵入性检测相结合用于对患者进行风险分层的基础。主要目标：1）阐明引发导致SCD的致命性心律失常的触发因素的分子基础; 2）建立基因型-表型相关性，可用于识别可能是更积极治疗候选者的心脏性猝死高风险个体。这种方法的基本原理是，了解心源性猝死触发因素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（行政，鼠标模型）。项目1将确定与心源性猝死风险增加相关的变异β-肾上腺素能受体（β AR）和兰尼碱受体（RyR）。项目2将研究RyR/细胞内钙释放通道的肾上腺素能调节在启动胎儿钙依赖性心律失常触发中的作用。项目3将使用与长Q-T综合征和Brugada综合征相关的心脏离子通道和/或信号传导分子的已识别人类突变作为范例，以检验离子通道活性变化可能改变细胞动作电位的构型的假设，这有助于钙稳态的变化，进而触发心肌活动。项目4将研究局部和整体钙信号的扰动在引发致命性心律失常中的作用。待检验的假设是离子通道和肾上腺素能介导的信号传导的扰动改变心肌细胞中的钙稳态，产生致命性心脏介导的信号传导的触发改变心肌细胞中的钙稳态，产生致命性心律失常的触发。所有四个项目的一个主要重点是确定引发地震事件的触发因素。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.