RhoA signaling pathway in stretch mediated cardiac hypertrophy

牵张介导的心脏肥大中的 RhoA 信号通路

• 批准号: 6564975
• 负责人: Robert Joel Schwartz
• 金额: $ 18.5万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6564975
• 关键词: biological signal transduction; cadherins; cardiac myocytes; enzyme activity; focal adhesion kinase; genetic transcription; genetically modified animals; guanine nucleotide binding protein; integrins; intracardiac pressure; laboratory mouse; laboratory rat; phosphatidylinositol 3 kinase; phosphorylation; stretch receptors; tissue /cell culture; transcription factor; ventricular hypertrophy

Understanding how cardiac myocytes transduce stretch signaling to alter nuclear transcriptional events will contribute greatly to our knowledge of the hierarchical mechanism which directs cardiac hypertrophy triggered by hypertension or structural heart disease. We propose the hypothesis that the effects of activated RhoA on the actin cytoskeleton and integrin activation might be the key mediator that links stretch dependent signaling to cardiac nuclear transcription factor performance, thus inducing cardiac hypertrophy in vivo. RhoA, a small molecular weight GTP-binding proteins acts a molecular switch that controls various cell functions and has received attention at a potential mediator of hypertrophic signals. The overall objective is to decipher the signaling pathways that link the potential receptors of the mechanical stretch signal to cytoskeleton assembly. and to the cardiac growth response. Aim I: to determine if stretch induces cardiac hypertrophy via activation of the RhoA signaling pathway in isolated cardiac myocytes. Aim II: to determine if focal adhesion kinase integrates the stretch signal through tyrosine auto-phosphorylation and/or by association with downstream signaling factors in isolate cardiac myocytes. Aim III: to determine if stretch activates integrin-linked kinase and if expression of kinase deficient of kinase deficient integrin-linked kinase attenuates cardiac hypertrophy facilitated by pressure overload. Aim IV: to determine the role of RhoA, focal adhesion kinase and integrin linked kinase and their mutated dominant negative species and whether they modify cardiac hypertrophic responses facilitated by pressure overload in inducible transgenic mouse models.

了解心肌细胞如何转导拉伸信号以改变核转录事件将极大地有助于我们了解高血压或结构性心脏病引发的心脏肥大的分层机制。我们提出这样的假设：激活的 RhoA 对肌动蛋白细胞骨架和整合素激活的影响可能是将拉伸依赖性信号传导与心脏核转录因子性能联系起来的关键介质，从而诱导体内心脏肥大。 RhoA 是一种小分子量 GTP 结合蛋白，作为控制各种细胞功能的分子开关，作为肥大信号的潜在介质而受到关注。总体目标是破译将机械拉伸信号的潜在受体与细胞骨架组装联系起来的信号通路。和心脏生长反应。目标 I：确定拉伸是否通过激活离体心肌细胞中的 RhoA 信号通路来诱导心脏肥大。目标 II：确定粘着斑激酶是否通过酪氨酸自磷酸化和/或通过与分离的心肌细胞中的下游信号因子关联来整合拉伸信号。目标 III：确定拉伸是否会激活整合素连接激酶，以及缺乏激酶的整合素连接激酶的表达是否会减弱压力超负荷导致的心脏肥大。目标 IV：确定 RhoA、粘着斑激酶和整联蛋白连接激酶及其突变的显性失活物种的作用，以及它们是否改变诱导转基因小鼠模型中由压力超负荷促进的心脏肥大反应。