RhoA signaling pathway in stretch mediated cardiac hypertrophy

了解心肌细胞如何转导拉伸信号来改变核转录事件，将有助于我们了解高血压或结构性心脏病引发的心肌肥厚的分级机制。我们提出的假设是，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信号与心肌核转录因子表现联系起来的关键中介，从而在体内诱导心肌肥大。RhoA是一种小分子GTP结合蛋白，起着分子开关的作用，控制着细胞的各种功能，是肥大信号的潜在中介。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。以及心脏生长反应。目的：研究牵张是否通过激活RhoA信号通路诱导心肌细胞肥大。目的II：在分离的心肌细胞中，确定粘着斑激酶是否通过酪氨酸自身磷酸化和/或与下游信号因子结合来整合拉伸信号。目的III：确定牵张是否激活整合素连接的激酶，以及表达缺失的整合素连接的激酶是否能减轻压力超负荷所致的心肌肥厚。目的：探讨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在可诱导转基因小鼠模型中的作用及其对压力超负荷所致心肌肥大反应的影响。

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.