Role of Integrins in Cardiac Myocyte Function

描述(申请人提供)：细胞外基质(ECM)是一种 心脏力学的重要决定因素。它通过以下方式发挥结构性作用 维护肌细胞和血管的排列，防止肌细胞 收缩过程中的滑移。ECM还发挥着积极的职能作用，如 力传感器。整合素是细胞外基质的主要受体，连接 细胞外基质与细胞内细胞骨架和激活信号 细胞外基质黏附反应的转导通路。他们是必不可少的 正常心脏发育、心肌细胞分化和肌节 集合。整合素不仅介导细胞黏附，而且还作为 生长因子的辅助受体刺激通路和作为机械转导。 我们假设整合素在细胞内作为重要的信号调节器发挥作用。 心脏感知和对机械和内分泌刺激的反应以维持 心脏止血。具体假设整合素信号转导 信号通路与G蛋白偶联受体的信号通路整合 (GPCR)协同调节心肌细胞肥大反应。 这项建议的目的是定义整合素介导的作用 黏附和信号在形态和转录变化中的作用 明确心肌细胞肥大反应途径。建议数 研究将利用一种具有良好特性的新生大鼠细胞培养模型 心肌细胞和腺病毒基因传递。首先，我们将确定 功能整合素变异体的得失表达对细胞因子表达的影响 心肌细胞组织和肥大标志物基因表达。第二, 我们将确定FAK在整合素介导的细胞变化中的作用 与心肌细胞肥大有关。第三，我们将确定 整合素信号偶联关系的机制基础 Gpr激动剂诱导的心肌细胞肥大反应。研究将寻求 确定gpr介导的信号转导和 整合素信号通路与整合素的关键效应分子 协同调节心脏肾上腺素能信号通路的信号转导 肌细胞。总体而言，这些研究将提供对分子的洞察 作为代偿性肥大生长反应基础的途径以及 向心力衰竭的过渡。对心肌细胞有更深入的了解 信号通路可能导致新的治疗方法适用于 在人类心肌中发现的病理改变。

DESCRIPTION (provided by applicant): The extracellular matrix (ECM) is an important determinant of cardiac mechanics. It plays a structural role by maintaining the alignment of myocytes and vessels and preventing myocyte slippage during contraction. ECM also plays an active functional role as a force transducer. Integrins, the predominant receptors for the ECM, link the extracellular matrix with the intracellular cytoskeleton and activate signal transduction pathways in response to ECM adhesion. They are essential for normal cardiac development, cardiomyocyte differentiation, and sarcomere assembly. Integrins not only mediate cell adhesion, but also serve as co-receptors for growth factor stimulated pathways and as mechanotransducers. We hypothesize that integrins function as important signaling modulators in the heart sensing and responding to mechanical and endocrine stimuli to maintain cardiac hemostasis. It is specifically hypothesized that integrin signaling pathways integrate with signaling pathways from G-protein coupled receptors (GPCR) to coordinately regulate the hypertrophic response of cardiac myocytes. The objective of this proposal is to define the role of integrin mediated adhesion and signaling in the morphological and transcriptional changes that define the hypertrophic response pathway of cardiac myocytes. The proposed studies will utilize a well characterized cell culture model of neonatal rat ventricular myocytes and adenoviral gene delivery. First, we will determine the effect of the expression of gain or loss of function integrin variants on myocyte cellular organization and hypertrophic marker gene expression. Second, we will determine the role of FAK in the integrin mediated cellular changes associated with cardiac myocyte hypertrophy. Third, we will determine the mechanistic basis of the relationship that couples integrin signaling to hypertrophic response in myocytes induced by GPCR agonists. Studies will seek to identify the point of convergence between GPCR mediated signaling and integrin signaling pathways and the critical effector molecules of integrin signaling that cooperatively regulate adrenergic signaling pathways in cardiac myocytes. Overall, these studies will provide insights into the molecular pathways that underlie the compensatory hypertrophic growth response as well as the transition to cardiac failure. A greater understanding of cardiac myocyte signaling pathways may lead to new therapeutic approaches applicable to pathologic alterations found in the human myocardium.