Molecular Basis of Sudden Cardiac Death

本研究申请心源性猝死项目资助（PPG），旨在通过遗传学、分子和细胞生物学以及生物物理学的结合，增强我们对心源性猝死的理解。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器。一个基本的前提是，对正常和病理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，也是基因型-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)阐明致死性心律失常诱发SCD的分子基础；2)建立基因型-表型相关性，可用于识别心源性猝死高风险个体，这些个体可能是更积极治疗的候选人。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（管理模型、鼠标模型）。项目1将鉴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 - aar）和ryanodine受体（RyR）。项目2将研究肾上腺素能调节RyR/细胞内钙释放通道在触发胎儿钙依赖性心律失常中的作用。项目3将使用已知的人类心脏离子通道和/或与Long Q-T综合征和Brugada综合征相关的信号分子突变作为范例来验证离子通道活性的变化可能改变细胞动作电位的配置，从而导致钙稳态的变化，进而引发心律失常活动的假设。项目4将研究局部和全局钙信号的扰动在致死性心律失常的启动触发中的作用。待验证的假设是离子通道和肾上腺素能介导的信号的扰动改变心肌细胞钙稳态，引发致死性心脏介导的信号改变心肌细胞钙稳态，引发致死性心律失常。这四个项目的一个主要重点是识别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.