RhoA signaling pathway in stretch mediated cardiac hypertrophy

了解心肌细胞如何通过伸展信号改变核转录事件，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级机制。我们提出的假设，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关键的介质，连接拉伸依赖性信号传导的心脏核转录因子的性能，从而诱导心肌肥大在体内。RhoA是一种小分子量的GTP结合蛋白，作为一种分子开关，控制着细胞的各种功能，并作为一种潜在的肥大信号介导者而受到关注。总的目标是破译的信号通路，连接机械拉伸信号的潜在受体的细胞骨架组装。以及心脏生长反应。目的一：确定牵张是否通过激活离体心肌细胞RhoA信号通路诱导心肌肥大。目标二：以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传导因子结合来整合拉伸信号。目标三：以确定拉伸是否激活整联蛋白连接的激酶，以及激酶缺陷型整联蛋白连接的激酶的表达是否减弱由压力超负荷促进的心脏肥大。目标四：以确定RhoA、粘着斑激酶和整合素连接激酶及其突变的显性负性物种的作用，以及它们是否在诱导型转基因小鼠模型中改变由压力超负荷促进的心脏肥大反应。

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.