Electrical Remodeling and Cardiac Hypertrophy and Signa*

电重塑和心脏肥大及信号*

• 批准号: 6886754
• 负责人: DJAMEL LEBECHE
• 金额: $ 13.53万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6886754
• 关键词: Adenoviridae; action potentials; biological signal transduction; calcineurin; calcium channel; calcium flux; electrical measurement; gene expression; heart electrical activity; heart failure; intracardiac pressure; laboratory rat; mitogen activated protein kinase; potassium channel; protein protein interaction; transfection; ventricular hypertrophy

DESCRIPTION (provided by applicant): Heart failure is a major cause of morbidity and mortality in the United States. The purpose of this Mentored Minority Faculty Development Award (K01) is to prepare the applicant for a career as an independent investigator in the area of cardiac hypertrophy and heart failure. The applicant has developed a great interest in the disorders of cardiac excitability and cellular dysfunction observed in heart failure. The applicant proposes to acquire additional skills in somatic gene transfer, electrophysiology and in vivo cardio-physiology in the context of a project that will promote the development of the intellectual skills necessary for success as an independent investigator. Heart failure is a highly lethal syndrome worldwide with as many as 50% of affected patients dying suddenly. At the cellular level, reduction of the calcium-independent transient outward current (Ito0 and prolongation of the action potential duration (APD) is consistently observed in experimental animal models of cardiac hypertrophy and failure and human heart failure. In hypertrophied myocytes Itol is decreased secondary to reductions in the expression of Kv4.2 and Kv4.3 potassium channel genes and more recently to the K channel interacting protein (KChlP2). The proposed project is intended to decipher the role of calcium entry via L-type calcium channels secondary to manipulation of the potassium channel genes encoding for Ito_ and the potassium channel interacting protein. We hypothesize that: 1) APD prolongation plays an important role in the progression of hypertrophy and failure once cardiac hypertrophy is initiated, 2) that elevations in systolic [Ca 2+] can activate the "stress signaling pathways" such as calcineurin and MAPKinase pathways leading to alterations in gene expression and hypertrophy, and 3) that the potassium channel interacting protein plays a an important modulatory role in the hypertrophic process. We will use adenoviral gene transfer to introduce Kv4.2, Kv4.3, and KChIP2 into aortic-banded rat hearts. We will measure electrophysiologic and Ca 2+ and hemodynamics parameters and use an animal model of pressure overload to determine the effects of 1) Kv channel and KChIP manipulation on Itol and APD in vitro and in vivo and 2) the signaling pathways on the response to hypertrophy and failure. Understanding the role of K+ channels in signal transduction will lead to the design of specific drugs to target these channels and block the development of hypertrophy and ultimately the regression from hypertrophy to failure.

描述（由申请人提供）： 心力衰竭是美国发病率和死亡率的主要原因。这个辅导少数民族教师发展奖（K 01）的目的是准备申请人的职业生涯作为一个独立的研究人员在心脏肥大和心力衰竭的领域。申请人对心力衰竭中观察到的心脏兴奋性和细胞功能障碍的病症产生了极大的兴趣。申请人建议在一个项目的背景下获得体细胞基因转移，电生理学和体内心脏生理学方面的额外技能，该项目将促进作为独立研究者成功所需的智力技能的发展。 心力衰竭是一种高致死性综合征，在全球范围内，多达50%的受影响患者会突然死亡。在细胞水平上，在心脏肥大和衰竭的实验动物模型以及人类心力衰竭中一致地观察到钙非依赖性瞬时外向电流（Ito 0）的减少和动作电位时程（APD）的延长。在肥大的肌细胞中，Itol的降低继发于Kv4.2和Kv4.3钾通道基因表达的降低，最近是K通道相互作用蛋白（KChIP 2）的降低。拟议的项目旨在破译钙通过L型钙通道进入的作用，这是对编码Ito和钾通道相互作用蛋白的钾通道基因进行操纵的第二步。我们假设：1）一旦心肌肥厚开始，APD延长在肥厚和衰竭的进展中起重要作用; 2）收缩期[Ca 2+]升高可激活“应激信号通路”，如钙调神经磷酸酶和MAP激酶通路，导致基因表达和肥厚的改变; 3）钾通道相互作用蛋白在肥厚过程中起重要的调节作用。 我们将使用腺病毒基因转移将Kv4.2，Kv4.3和KChIP 2引入到大鼠心脏中。我们将通过测量电生理、Ca 2+和血流动力学参数，并利用压力超负荷动物模型，研究1）Kv通道和KChIP操作在体内外对Itol和APD的影响; 2）信号通路在肥大和衰竭反应中的作用。了解K+通道在信号转导中的作用将导致设计特异性药物来靶向这些通道并阻断肥大的发展，并最终从肥大回归到失败。