Akt activation to treat heart failure

描述（由申请人提供）：保护心肌组织免受凋亡细胞死亡和不适应肥厚重塑是抑制发病机制和减缓向心力衰竭过渡的有效方法。尽管对心肌存活信号通路的了解越来越详细和具体，但利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目前对心肌细胞如何以适当调节的方式解释细胞外刺激并将其转化为有利的生存信号的理解的局限性。这项研究的长期目标是了解心肌细胞中心肌保护信号的分子机制。本研究的目的是证明通过Akt激酶介导的心肌信号传导可以有效地提高心肌细胞的存活率，抑制心肌病损伤，而不会产生病理副作用。具体而言，实验旨在定义和优化促进Akt核积累的机制，并证明其抑制心肌病重塑的功效。我们的假设是，Akt的核积累可以被诱导和控制，以抑制病理损伤引起的心肌病变化。该提案的具体目标将证明：1)核Akt积累介导抗肥厚作用，2)Akt在细胞核中的积累对有益的心脏保护作用至关重要，3)核靶向Akt的急性表达增强心肌病损伤的恢复，4)Akt的核积累是由C-LIM蛋白zyxin和paxillin介导的。采用的创新方法将包括对培养的心肌细胞和小鼠模型进行分子、生化和显微镜分析，通过心脏保护刺激、重组腺病毒和转基因小鼠系来优化Akt的核积累。这些研究的意义在于建立akt介导的心肌细胞心脏保护信号传导机制，明确akt核转运的机制，并证明干预方法对akt介导的信号转导的调节作用，以适当有益的方式提高心肌细胞的存活率。

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.