Electrical Remodeling and Cardiac Hypertrophy and Signa*

电重塑和心脏肥大及信号*

• 批准号: 7052769
• 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 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7052769
• 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。这个有指导的少数族裔教师发展奖(K01)的目的是为申请者在心脏肥厚和心力衰竭领域作为一名独立研究员的职业生涯做好准备。申请人对在心力衰竭中观察到的心脏兴奋性和细胞功能障碍的障碍产生了极大的兴趣。申请人提议在一个项目的背景下获得身体基因转移、电生理学和活体心脏生理学方面的更多技能，该项目将促进发展成为一名独立研究人员所必需的智力技能。 心力衰竭是世界范围内的一种高度致命的综合征，多达50%的受影响患者突然死亡。在细胞水平上，在心肌肥厚和衰竭的实验动物模型和人类心力衰竭模型中，一致地观察到钙非依赖性瞬时外向电流(Ito0)的减少和动作电位时程(APD)的延长。在肥大的心肌细胞中，由于Kv4.2和Kv4.3钾通道基因的表达减少，以及最近K通道相互作用蛋白(KChlP2)的表达减少，Itol减少。该项目旨在破译编码Ito_的钾通道基因和钾通道相互作用蛋白之后，通过L类型的钙通道进入钙通道的作用。我们推测：1)当心肌肥厚发生时，动作电位时程延长在肥厚和衰竭的发展过程中起重要作用；2)收缩期[Ca2+]升高可以激活“应激信号通路”，如钙调神经磷酸酶和MAPKinase通路，导致基因表达改变和肥厚；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KChIP2导入主动脉结扎的大鼠心脏。我们将测量电生理、钙离子和血流动力学参数，并使用压力超负荷的动物模型来确定1)Kv通道和KChIP手法在体内外对Itol和时程的影响；2)信号通路在肥厚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针对这些通道的特定药物的设计，并阻止肥大的发展，最终阻止肥厚向衰竭的回归。