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RHOA KINASES IN CARDIAC HYPERTROPHY

心脏肥大中的 RHOA 激酶

基本信息

批准号：
6629074
负责人：
Robert Joel Schwartz
金额：
$ 42.56万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-02-04 至 2004-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6629074
关键词：
DNA binding protein G protein coupled receptor kinase biological signal transduction cardiac myocytes gene expression genetically modified animals guanine nucleotide binding protein integrins laboratory mouse laboratory rat molecular pathology phosphorylation stretch receptors tissue /cell culture ventricular hypertrophy

项目摘要

The mechanisms directing cardiac hypertrophy, triggered by hemodynamic overload and/or structural heart disease, are still not completely understood. Delineating how cardiac myocytes transduce mechanical stress related signaling from the membrane to nuclear transcription will greatly contribute to our understanding of the clinical problems of cardiac hypertrophy. RhoA, a small molecular weight GTP- binding protein, acts as a molecular switch that controls various cell functions, and is a potential mediator of hypertrophic signals. We hypothesize that RhoA functions as a key transducer in the induction cascade that links stretch dependent signaling to the induction of cardiac gene expression in vivo. In addition, we propose that the Ser/Thr kinase P160rock, recently identified as a downstream effector of Rho1A, is the primary signaling molecule mediating hypertrophic effects of RhoA. Our preliminary results indicate that RhoA and p160ROCK, together with beta1 integrin and its adhesion dependent actions, serve as a novel signal pathway in activating the cardiac enriched serum response factor (SRF) dependent genes in cardiomyocytes, such as skeletal alpha-actin, through the p160ROCK dependent phosphorylation of SRF. We have also observed that the level of p160ROCK mRNA transcripts is markedly induced in the overloaded heart, suggesting an important role for this molecule in the development of cardiac hypertrophy. Our results suggest that phosphorylation of SRF by 160ROCK might be a critical step for the activation of fetal cardiac gene expression during cardiac hypertrophy. The Specific Aims of this proposal are: 1) to determine the role of RhoA, p160ROCK and SRF in mediating hypertrophic responses induced by stretch in cultured cardiomyocytes; 2) to determine if the RhoA signaling pathways regulates SRF-dependent hypertrophic gene expression via phosphorylation of SRF by 160ROCK; 3) to determine the role of RhoA and p160ROCK in mediating cardiac hypertrophic responses induced by pressure overload in genetically manipulated mouse models. The overall objective is to determine if RhoA, beta1 integrin, p160ROCK and SRF are primary mediators of a potentially important novel signal pathway that contributes to reprogramming of cardiomyocyte gene expression in stretch induced cardiac hypertrophy.

由血流动力学超负荷和/或结构性心脏病引发的心脏肥大的机制尚不完全清楚。描述心肌细胞如何将机械应力相关信号从膜转导到核转录将极大地有助于我们理解心脏肥大的临床问题。 RhoA 是一种小分子量 GTP 结合蛋白，充当控制各种细胞功能的分子开关，并且是肥大信号的潜在介质。我们假设 RhoA 作为诱导级联中的关键转导器，将拉伸依赖性信号传导与体内心脏基因表达的诱导联系起来。此外，我们提出最近被鉴定为 Rho1A 下游效应器的 Ser/Thr 激酶 P160rock 是介导 RhoA 肥大作用的主要信号分子。我们的初步结果表明，RhoA 和 p160ROCK 与 β1 整联蛋白及其粘附依赖性作用一起，通过 p160ROCK 依赖性 SRF 磷酸化，作为激活心肌细胞中心脏富集血清反应因子 (SRF) 依赖性基因（例如骨骼 α-肌动蛋白）的新信号途径。我们还观察到，在超负荷的心脏中，p160ROCK mRNA 转录物的水平被显着诱导，表明该分子在心脏肥大的发展中发挥着重要作用。我们的结果表明，160ROCK 对 SRF 的磷酸化可能是心脏肥大期间激活胎儿心脏基因表达的关键步骤。该提案的具体目标是： 1) 确定 RhoA、p160ROCK 和 SRF 在介导培养心肌细胞拉伸诱导的肥大反应中的作用； 2)确定RhoA信号通路是否通过160ROCK磷酸化SRF来调节SRF依赖性肥大基因表达； 3) 确定RhoA和p160ROCK在介导基因操纵小鼠模型中压力超负荷引起的心脏肥大反应中的作用。总体目标是确定 RhoA、β1 整合素、p160ROCK 和 SRF 是否是潜在重要的新型信号通路的主要介质，该信号通路有助于在牵拉诱导的心脏肥大中心肌细胞基因表达的重新编程。