REGULATION OF CARDIOMYOCYTE SURVIVAL

心肌细胞存活的调节

基本信息

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
项目类别：
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

项目摘要

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）是儿童时期的常见事件，具有显着的发病率和死亡率。目前的研究表明心肌细胞凋亡可能对心力衰竭的发生有重要影响。我们有最近证明 ROCK1（Rho 相关的卷曲螺旋蛋白激酶 1）是一个关键将促凋亡刺激与新生儿心肌细胞凋亡联系起来的介质。我们的结果表明模型中，低水平的活化 caspase 3 直接裂解并激活 ROCK1；激活ROCK1 转角放大了 caspase 3 的激活，导致心脏细胞凋亡显着放大。重要的是，这 ROCK1 激活和 caspase 3 激活之间的机制关系发生在衰竭的人类心脏中，表明该途径是有效的治疗靶点。项目2中提出的实验将进一步验证 ROCK1 介导的重要性并建立其机制基础心肌细胞凋亡。具体目标 1 将描述 ROCK1 激活在心肌细胞中的作用细胞凋亡。初步实验将确定 caspase 3 依赖性 ROCK1 激活对使用心脏毒性药物治疗后心肌细胞存活和心力衰竭进展童年期心力衰竭。其他研究将检验 ROCK1 激活足以放大 caspase 3 的假设激活并诱导体内心肌细胞凋亡。具体目标 2 中提出的实验将建立激活的ROCK1诱导心肌细胞凋亡的分子机制。最初的研究将验证以下假设：激活的 ROCK1 通过线粒体后放大 caspase 3 的激活规定。其他研究将确定基于 TAT 的抗凋亡蛋白递送是否可以减弱在体外激活 ROCK1 诱导的心肌细胞凋亡，如果有必要，在体内也可以激活。总的来说，项目 2 中提出的实验将检验 ROCK1 介导的 caspase 3 扩增这一假设 ROCK1的激活在心肌细胞凋亡中起着至关重要的作用，并且进一步确立了ROCK1的作用响应导致儿童心力衰竭的获得性心肌损伤的信号传导。该项目还将确定是否可以利用 ROCK1 信号传导来治疗性抑制心肌细胞获得性出生后心力衰竭小鼠模型中的细胞凋亡。