Integrin signaling in stretch-induced regulation of Cx43

描述（由申请人提供）：关于整合素介导的机械电耦合在心肌细胞中的作用知之甚少。拟议的研究项目旨在阐明整合素/粘着斑激酶（FAK）信号转导在新生大鼠心室肌细胞中牵张和化学介导的Cx43上调中的作用。我也将测试的假设，即肌细胞的结构和功能，部分决定了肌细胞和特定的细胞外基质（ECM）蛋白之间的相互作用。在具体目标1中，我将描述在有和没有单向脉动拉伸的情况下，在不同ECM蛋白上生长的肌细胞中Cx43表达的水平和模式。在具体目标2中，我将确定是否整合素介导的FAK激活有助于牵张诱导的上调Cx43的心肌细胞。在具体目标3中，我将确定血管内皮生长因子（VEGF）是否在肌细胞中牵张介导的Cx43上调中作用于FAK下游。在具体目标4中，我将确定牵张的化学介质（VEGF，血管紧张素II）是否改变肌细胞中整合素表达的水平和模式。这些研究结果将为心肌肥厚中细胞间偶联和传导的调节机制提供新的见解。

DESCRIPTION (provided by applicant): Little is known about the role of integrin-mediated mechanoelectrical coupling in cardiac myocytes. The proposed research project is designed to elucidate the role of integrin/focal adhesion kinase (FAK) signaling in stretch- and chemically- mediated up-regulation of Cx43 in neonatal rat ventricular myocytes. I will also test the hypothesis that myocyte structure and function is partly determined by interactions between myocytes and specific extracellular matrix (ECM) proteins. In Specific Aim 1, I will characterize the levels and patterns of Cx43 expression in myocytes grown on different ECM proteins with and without uni-directional pulsatile stretch. In Specific Aim 2, I will determine whether integrin-mediated FAK activation contributes to stretch-induced up-regulation of Cx43 in myocytes. In Specific Aim 3, I will determine if vascular endothelial growth factor (VEGF) acts downstream of FAK in stretch-mediated up-regulation of Cx43 in myocytes. In Specific Aim 4, I will determine if chemical mediators of stretch (VEGF, Angiotensin II) alter levels and patterns of integrin expression in myocytes. The results of the proposed studies will provide new insights into mechanisms regulating intercellular coupling and conduction in cardiac hypertrophy.