Molecular mechanisms of electrical remodeling in cardiac hypertrophy

描述(由申请人提供)： 这笔赠款将支持为期5年的严格培训，以促进职业生涯的发展 学术心脏电生理学的独立研究员。首席调查员已经完成了 他在马萨诸塞州总医院担任心脏病学和电生理学的临床研究员，并寻求 通过独特的资源整合，拓展他的科学技能。这项提案旨在调查 伴随心肌肥厚的电重构机制。候选人将受到 贝斯以色列医院心血管研究主任安东尼·罗森茨韦格博士的联合指导 女执事医学中心，她在心肌肥厚和激酶信号领域拥有专业知识 帕特里克·埃利诺博士，麻省理工学院医学助理教授，在以下领域拥有专业知识 心脏离子通道结构-功能。一个既包括研究又包括教学培训的课程将 旨在进一步培训候选人，并成立一个由领先医学研究人员组成的咨询委员会 将提供科学和职业建议。 心脏性猝死和室性心律失常(VA)是慢性阻塞性肺疾病患者死亡的主要来源 充血性心力衰竭心肌肥厚是心力衰竭的先兆，是心力衰竭的独立预测因子 VAS。然而，将肥大与电重构联系起来的信号级联包括 底物是致死性VAS的诱因，目前还不是很清楚。我们最近展示了 依赖PI-3的血清糖皮质激素反应激酶(SGK-1)对心脏的调节作用 对不同刺激反应的肥大。SGK-1独一无二地针对几个离子通道，我们的新和 令人兴奋的初步数据表明，SGK-1可以磷酸化并改变电压门控信号的运输 心肌细胞中的心脏钠通道SCNSa。该提案的总体目标是检验这一假设 SGK-1是心肌肥厚电重构的重要介导物。 遵循特定的目标。我们建议1)确定SGK-1对于 肥大引起的SCNSa改变。2)研究SGK-1在SCNSa调控中的作用 功能，以及3)评估SGK-1是否是与心脏相关的电重构的介质 肥大。这些目标将通过生物化学、分子生物学和 电生理学技术的体外和体内研究的小鼠接受基因操作。 这些目标的完成将提供对心脏电的分子基础的更深层次的理解 改建。对肥厚和电重构之间关键机制联系的洞察可能 在一个具有重要临床意义的领域带来了更新的治疗选择。此外，这项提议将有助于 作为候选人过渡到独立调查员的理想平台。

DESCRIPTION (provided by applicant): This grant will support a 5-year period of rigorous training for the development of a career as an independent investigator in academic cardiac electrophysiology. The principal investigator has completed his clinical fellowship in cardiology and electrophysiology at Massachusetts General Hospital and seeks to expand his scientific skills using a unique integration of resources. This proposal seeks to investigate the mechanisms of electrical remodeling that accompany cardiac hypertrophy. The candidate will be under the joint mentorship of Dr. Anthony Rosenzweig, the Director of Cardiovascular Research at Beth Israel Deaconess Medical Center, who has expertise in the field of cardiac hypertrophy and kinase signaling pathways, and Dr. Patrick Ellinor, Assistant Professor of Medicine at MGH, who has expertise in the field of cardiac ion channel structure-function. A curriculum encompassing both research and didactic training will be devised to further the training of the candidate, and an advisory committee of leading medical researchers will provide scientific and career advice. Sudden cardiac death and ventricular arrhythmias (VA) are a leading source of mortality in patients with congestive heart failure. Myocardial hypertrophy precedes heart failure and is an independent predictor of VAs. However, the signaling cascades that link hypertrophy to the electrical remodeling that comprises the substrate and is the source of triggers of lethal VAs are not well understood as yet. We have recently shown that the PI-3 kinase-dependent serum glucocorticoid-responsive kinase (SGK-1) can modulate cardiac hypertrophy in response to diverse stimuli. SGK-1 uniquely targets several ion channels, and our new and exciting preliminary data suggest that SGK-1 can phosphorylate and alter the trafficking of the voltage-gated cardiac sodium channel SCNSa in cardiomyocytes. The overall goal of the proposal is to test the hypothesis that SGK-1 is an important mediator of the electrical remodeling in cardiac hypertrophy by addressing the following specific aims. We propose 1) To determine if SGK-1 is necessary and sufficient for hypertrophy-induced changes in SCNSa. 2) To examine the role of SGK-1 in regulation of SCNSa function, and 3) To evaluate if SGK-1 is a mediator of electrical remodeling associated with cardiac hypertrophy. These aims will be achieved using a combination of biochemical, molecular biological and electrophysiological techniques in vitro as well as by in vivo studies in mice subject to genetic manipulation. Completion of these aims will provide a deeper understanding of the molecular basis of cardiac electrical remodeling. Insights into the critical mechanistic links between hypertrophy and electrical remodeling may lead to newer therapeutic options in an area of great clinical importance. Furthermore the proposal will serve as an ideal platform for the candidate to make the transition to an independent investigator.