Molecular mechanisms of electrical remodeling in cardiac hypertrophy

心脏肥大电重塑的分子机制

• 批准号: 7470840
• 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
• 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/7470840
• 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; Depth; 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

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）： 该赠款将支持5年的严格培训，以发展职业 学术心脏生理学的独立研究者。首席调查员已经完成 他在马萨诸塞州综合医院在心脏病学和电生理学方面的临床奖学金，并寻求 使用独特的资源整合来扩展他的科学技能。该建议旨在调查 伴随心脏肥大的电重塑的机制。候选人将在 贝丝以色列心血管研究主任安东尼·罗森斯维格（Anthony Rosenzweig）的联合指导 执事医疗中心，他在心脏肥大和激酶信号领域具有专业知识 Pathways和MGH医学助理教授Patrick Ellinor博士，他在该领域具有专业知识 心脏离子通道结构功能。涵盖研究和教学培训的课程将 设计为进一步培训候选人和领先的医学研究人员的咨询委员会 将提供科学和职业建议。 心脏猝死和心室心律失常（VA）是患者的主要死亡率来源 充血性心力衰竭。心肌肥大先于心力衰竭，是 VAS。但是，将肥大链接到电气重塑的信号传导级联反应包括 底物，是致命VA的触发器的来源，尚未很好地理解。我们最近显示了 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 肥大响应多种刺激。 SGK-1唯一针对几个离子渠道，以及我们的新渠道 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 该SGK-1是通过解决心脏肥大的电气重塑的重要介体 遵循特定目标。我们建议1）确定SGK-1是否需要且足够 肥大引起的SCNSA变化。 2）检查SGK-1在SCNSA调节中的作用 功能和3）评估SGK-1是否是与心脏相关的电重塑的介体 肥大。这些目标将通过生化，分子生物学和 在体外以及通过基因操纵的小鼠中的体内研究中的电生理技术。 这些目标的完成将为心脏电气的分子基础提供更深入的了解 重塑。对肥大与电重塑之间关键机理联系的见解可能 在临床重要性的领域中导致更新的治疗选择。此外，该提案将服务 作为候选人将过渡到独立调查员的理想平台。