Akt activation to treat heart failure

Akt 激活治疗心力衰竭

基本信息

批准号：
6989171
负责人：
MARK ALAN SUSSMAN
金额：
$ 37.5万
依托单位：
SAN DIEGO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-06-01 至 2010-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Protection of myocardial tissue from apoptotic cell death and maladaptive hypertrophic remodeling are valid approaches to inhibit pathogenesis and slow the transition to heart failure. Despite increasingly detailed and specific knowledge of survival signaling pathways in the myocardium, the potential promise of beneficial interventional approaches using this knowledge remains unfulfilled. This failure stems, in part, from limitations in our current understanding of how cardiomyocytes interpret extracellular stimuli translate this into advantageous survival signaling in an appropriately regulated fashion. The long term goal of this study is to understand molecular mechanism(s) responsible for cardioprotective signaling in cardiomyocytes. The goal of this proposal is to demonstrate that myocardial signaling through Akt kinase can be manipulated beneficially to enhance cardiomyocyte survival and inhibit cardiomyopathic damage without pathologic side effects. Specifically, experiments are designed to define and optimize mechanisms to promote nuclear accumulation of Akt together with demonstration of efficacy at inhibiting cardiomyopathic remodeling. The hypothesis is that nuclear accumulation of Akt can be induced and controlled in order to inhibit cardiomyopathic changes in response to pathologic insults. Specific aims of the proposal will demonstrate that: 1) nuclear Akt accumulation mediates anti-hypertrophic effects, 2) accumulation of Akt in the nucleus is critical for beneficial cardioprotective action, 3) acute expression of nuclear-targeted Akt potentiates recovery from cardiomyopathic insults, and 4) nuclear accumulation of Akt is mediated by the C-LIM proteins zyxin and paxillin. The innovative approach employed will involve molecular, biochemical, and microscopic analyses of cultured cardiomyocytes and mouse models manipulated to optimize nuclear accumulation of Akt by cardioprotective stimuli, recombinant adenoviruses, and genetically engineered transgenic mouse lines. The significance of these studies is to establish the mechanism of Akt-mediated cardioprotective signaling in cardiomyocytes, define the mechanism of Akt-nuclear trafficking, and demonstrate the efficacy of interventional approaches to regulate Akt-mediated signal transduction and enhance cardiomyocyte survival in an appropriately beneficial fashion.

描述（由申请人提供）：对心肌组织免受凋亡细胞死亡和不良适应性肥厚性重塑的保护是抑制发病机理并减慢心力衰竭过渡的有效方法。尽管对心肌中生存信号通路的详细和具体知识越来越详细，但使用这些知识的有益介入方法的潜在希望仍然没有实现。这种失败部分源于我们当前对心肌细胞如何解释细胞外刺激的局限性，以适当调节的方式将其转化为有利的生存信号。这项研究的长期目标是了解负责心肌细胞心脏保护信号传导的分子机制。该提案的目的是证明可以通过AKT激酶进行心肌信号传导，以实现有益地操纵以增强心肌细胞的存活并抑制心肌性损伤而没有病理副作用。具体而言，实验旨在定义和优化机制，以促进AKT的核积累，并在抑制心肌病重塑时表现出疗效。假设是，可以诱导和控制AKT的核积累，以抑制心肌病的变化，以应对病理损伤。 Specific aims of the proposal will demonstrate that: 1) nuclear Akt accumulation mediates anti-hypertrophic effects, 2) accumulation of Akt in the nucleus is critical for beneficial cardioprotective action, 3) acute expression of nuclear-targeted Akt potentiates recovery from cardiomyopathic insults, and 4) nuclear accumulation of Akt is mediated by the C-LIM proteins zyxin and帕克西林。所采用的创新方法将涉及对培养的心肌细胞和小鼠模型进行的分子，生化和微观分析，这些模型操纵以优化通过心脏保护刺激，重组腺病毒和基因工艺的转基因小鼠线来优化Akt的核积累。这些研究的重要性是建立心肌细胞中Akt介导的心脏保护信号传导的机制，定义Akt核贩运的机制，并证明了介入AKT介导的信号转导和增强心肌细胞在适当的有益外观中的介入信号转导的疗效。