REGULATION OF CARDIOMYOCYTE SURVIVAL

心肌细胞存活的调节

• 批准号: 7901822
• 负责人: Lei Wei
• 金额: $ 35.85万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7901822
• 关键词: Apoptosis; Apoptotic; Attenuated; Cardiac; Cardiac Myocytes; Cell Survival; Cessation of life; Child; Childhood; Cleaved cell; Clinical; Congenital Heart Defects; Development; Developmental Biology; Event; Gene Expression; Genetic; Growth; Heart; Heart failure; Human; Hyperplasia; In Vitro; Injury; Laboratories; Lead; Link; Mediating; Mediator of activation protein; Methodology; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Myocardial; Myocardial tissue; Myocardium; Natural regeneration; Neonatal; Pathway interactions; Pediatric Research; Pharmaceutical Preparations; Play; Productivity; Program Research Project Grants; Proteins; Reagent; Regulation; Research; Research Personnel; Risk; Role; Signal Transduction; Signal Transduction Pathway; Stimulus; Testing; Therapeutic Intervention; Translations; base; caspase-3; cell growth; cytokine; human ROCK1 protein; in vivo; mortality; mouse model; postnatal; programs; research study; response; skills; therapeutic target; transcription factor

Heart Failure (HF) is a common event in childhood with significant morbidity and mortality. Current research indicates that cardiomyocyte apoptosis may contribute significantly to the development of HF. We have recently demonstrated that ROCK1 (Rho-associated, coiled-coil containing protein kinase 1) is a key mediator which links pro-apoptotic stimuli to apoptosis in neonatal cardiomyocytes. Our results suggest a model wherein low levels of activated caspase 3 directly cleave and activate ROCK1; activated ROCK1 in turn amplifies caspase 3 activation, resulting in a marked amplification of cardiac apoptosis. Importantly, this mechanistic relationship between ROCK1 activation and caspase 3 activation occurs in failing human hearts, suggesting that this pathway is a valid therapeutic target. The experiments proposed in Project 2 will further validate the importance of, as well as establish the mechanistic underpinnings of, ROCK1-mediated cardiomyocyte apoptosis. Specific Aim 1 will characterize the role of ROCK1 activation in cardiomyocyte apoptosis. Initial experiments will establish the importance of caspase 3-dependent ROCK1 activation on cardiomyocyte survival and HF progression following treatment with cardiotoxic drugs which induce childhood HF. Other studies will test the hypothesis that ROCK1 activation is sufficient to amplify caspase 3 activation and induce cardiomyocyte apoptosis in vivo. Experiments proposed in Specific Aim 2 will establish the molecular mechanism by which activated ROCK1 induces cardiomyocyte apoptosis. Initial studies will test the hypothesis that activated ROCK1 amplifies caspase 3 activation via post-mitochondrial regulation. Other studies will determine if TAT-based delivery of anti-apoptotic proteins can attenuate activated ROCK1-induced cardiomyocyteapoptosis in vitro, and if warranted, in vivo. Collectively, the experiments proposed in Project 2 will test the hypothesis that ROCK1-mediated amplification of caspase 3 activation plays a critical role in cardiomyocyte apoptosis, and furthermore will establish the role of ROCK1 signaling in response to acquired myocardial injuries which lead to childhood HF. This project will also determine if manipulation of ROCK1 signaling can be exploited to therapeutically inhibit cardiomyocyte apoptosis in a mouse model of acquired postnatal HF.

心力衰竭（HF）是童年时期的常见事件，具有明显的发病率和死亡率。当前的研究 表明心肌细胞凋亡可能对HF的发展产生重大贡献。我们有 最近证明了岩石1（Rho相关的，含有蛋白质激酶1的卷曲卷头）是钥匙 将促凋亡刺激与新生儿心肌细胞凋亡联系起来的介体。我们的结果表明 模型中，低水平的激活caspase 3直接裂解并激活岩石1；激活的Rock1 in 转向放大caspase 3激活，导致心脏凋亡的显着扩增。重要的是，这个 Rock1激活与caspase 3激活之间的机械关系发生在失败的人心中， 表明该途径是有效的治疗靶标。项目2中提出的实验将进一步 验证岩石1介导的机械基础的重要性以及建立机械基础 心肌细胞凋亡。特定的目标1将表征岩石1激活在心肌细胞中的作用 凋亡。最初的实验将确定caspase 3依赖性岩石激活在上的重要性 心肌细胞的生存和HF进展，用心脏毒性药物诱导 童年时期。其他研究将检验以下假设：Rock1激活足以扩增caspase 3 激活并诱导体内心肌细胞凋亡。在特定目标2中提出的实验将 建立通过激活的岩石1诱导心肌细胞凋亡的分子机制。最初的 研究将测试激活岩石1的假设通过线粒体后的caspase 3激活 规定。其他研究将确定基于TAT的抗凋亡蛋白的递送是否可以减弱 活化的岩石1诱导的心肌细胞吞吐作用，如果有必要，则在体内。集体， 项目2中提出的实验将检验以下假设：岩石介导的caspase 3的扩增 激活在心肌细胞凋亡中起着至关重要的作用，此外将确定Rock1的作用 发出的信号是对获得的心肌损伤的响应，导致儿童HF。这个项目也将 确定是否可以利用Rock1信号的操纵来抑制心肌细胞 在获得后HF的小鼠模型中凋亡。