Akt activation to treat heart failure

描述（由申请方提供）：保护心肌组织免于凋亡性细胞死亡和适应不良的肥厚性重塑是抑制发病机制和减缓向心力衰竭转变的有效方法。尽管越来越详细和具体的知识，在心肌中的生存信号通路，潜在的承诺，有益的介入方法，利用这些知识仍然没有实现。这种失败部分源于我们目前对心肌细胞如何解释细胞外刺激的理解存在局限性，这些细胞外刺激以适当调节的方式将其转化为有利的生存信号。本研究的长期目标是了解心肌细胞中心脏保护信号的分子机制。该提案的目标是证明通过Akt激酶的心肌信号传导可以被有利地操纵以增强心肌细胞存活并抑制心肌病损伤而没有病理副作用。具体地，设计实验以定义和优化促进Akt的核积累的机制，以及证明抑制心肌病性重塑的功效。假设Akt的核积累可以被诱导和控制，以抑制响应于病理性损伤的心肌病变化。该提案的具体目的将证明：1）核Akt积累介导抗肥大作用，2）Akt在核中的积累对于有益的心脏保护作用是关键的，3）核靶向Akt的急性表达增强从心肌病损伤中的恢复，以及4）Akt的核积累由C-LIM蛋白质zyxin和桩蛋白介导。所采用的创新方法将涉及培养的心肌细胞和小鼠模型的分子，生物化学和显微镜分析，以优化Akt的核积累的心脏保护刺激，重组腺病毒和基因工程转基因小鼠品系。这些研究的意义在于建立心肌细胞中Akt介导的心脏保护信号传导的机制，定义Akt-核运输的机制，并证明干预方法调节Akt介导的信号转导并以适当有益的方式增强心肌细胞存活的功效。

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.