Molecular mechanisms of electrical remodeling in cardiac hypertrophy

心脏肥大电重塑的分子机制

基本信息

批准号：
7765574
负责人：
Saumya Das
金额：
$ 13.64万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7765574
关键词：
1-Phosphatidylinositol 3-Kinase Action Potentials Address Adult Advisory Committees Animals Area Biochemical Biological Cardiac Cardiac Myocytes Cardiology Cardiovascular system Cells Clinical Congestive Heart Failure Data Development Dominant-Negative Mutation Echocardiography Educational Curriculum Electrophysiology (science)Event Fellowship Future General Hospitals Glucocorticoids Goals Grant Heart Heart Hypertrophy Heart failure Hypertrophy In Vitro Ion Channel Israel Joints Lead Link Massachusetts Mediator of activation protein Medical Medical center Medicine Mentorship Modeling Molecular Mus Myocardial Nature Neonatal Patients Phosphorylation Phosphotransferases Plasmids Potassium Principal Investigator Property Proteins Rattus Regulation Research Research Personnel Resources Role Serum Signal Pathway Signal Transduction Sodium Sodium Channel Source Stimulus Structure Techniques Testing Tetrodotoxin Tissues Training Transgenic Animals Transgenic Mice Transgenic Organisms Ventricular Arrhythmia Virus base career electrical property genetic manipulation hemodynamics in vivo insight mortality novel therapeutics patch clamp pressure professor programs research study response skills stressor sudden cardiac death trafficking voltage

项目摘要

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.

描述（由申请人提供）：这笔赠款将支持为期 5 年的严格培训，以促进职业发展学术心脏电生理学的独立研究者。主要研究者已完成他在马萨诸塞州总医院获得心脏病学和电生理学临床奖学金，并寻求利用独特的资源整合来扩展他的科学技能。该提案旨在调查伴随心脏肥大的电重塑机制。候选人将根据贝斯以色列心血管研究主任 Anthony Rosenzweig 博士的联合指导女执事医疗中心，在心脏肥大和激酶信号传导领域拥有专业知识麻省总医院 (MGH) 医学助理教授帕特里克·埃利诺 (Patrick Ellinor) 博士在以下领域拥有专业知识心脏离子通道的结构-功能。涵盖研究和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。心源性猝死和室性心律失常 (VA) 是心律失常患者死亡的主要原因充血性心力衰竭。心肌肥厚先于心力衰竭，是心力衰竭的独立预测因素 VA。然而，将肥大与电重塑联系起来的信号级联，包括底物以及致命 VA 的触发源目前尚不清楚。我们最近展示了 PI-3 激酶依赖性血清糖皮质激素反应激酶 (SGK-1) 可以调节心脏对不同刺激的反应而肥大。 SGK-1 独特地针对多个离子通道，我们的新产品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蛋白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假设 SGK-1 是心脏肥大中电重塑的重要介质，通过解决遵循特定目标。我们建议 1) 确定 SGK-1 是否是必要且充分的肥大引起的 SCNSa 变化。 2) 考察SGK-1在SCNSa调节中的作用功能，以及 3) 评估 SGK-1 是否是与心脏相关的电重构的介质肥大。这些目标将通过结合生物化学、分子生物学和体外电生理技术以及对经过基因操作的小鼠进行体内研究。完成这些目标将有助于更深入地了解心电的分子基础重塑。深入了解肌肥大和电重塑之间的关键机制联系可能会有所帮助。在具有重要临床意义的领域带来更新的治疗选择。此外，该提案将服务于作为候选人过渡到独立调查员的理想平台。