Integrin signaling in stretch-induced regulation of Cx43

描述（由申请人提供）：关于整合素介导的心肌细胞机电偶联的作用知之甚少。该研究项目旨在阐明整合素/局灶黏着激酶（FAK）信号在新生儿大鼠心室肌细胞中拉伸和化学介导的Cx43上调中的作用。我还将验证肌细胞结构和功能部分由肌细胞和特定细胞外基质（ECM）蛋白之间的相互作用决定的假设。在Specific Aim 1中，我将描述在不同ECM蛋白上生长的肌细胞中有或没有单向脉冲拉伸的Cx43表达的水平和模式。在Specific Aim 2中，我将确定整合素介导的FAK激活是否有助于拉伸诱导肌细胞中Cx43的上调。在Specific Aim 3中，我将确定血管内皮生长因子（VEGF）是否在FAK的下游作用于拉伸介导的肌细胞Cx43的上调。在Specific Aim 4中，我将确定拉伸的化学介质（VEGF，血管紧张素II）是否会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的细胞间耦合和传导调控机制提供新的见解。

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.