Role of Integrins in Cardiac Myocyte Function

整合素在心肌细胞功能中的作用

• 批准号: 6527773
• 负责人: JOSEPH C LOFTUS
• 金额: $ 26.95万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6527773
• 关键词: G protein coupled receptor kinase; adrenergic receptor; biological signal transduction; cardiac myocytes; cell adhesion; cell growth regulation; extracellular matrix; focal adhesion kinase; hypertrophy; integrins; laboratory rat; newborn animals; tissue /cell culture; transfection

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.

描述（由申请人提供）：细胞外基质（ECM）是 心脏力学的重要决定因素。它扮演着结构上的角色 保持心肌细胞和血管的对齐并预防心肌细胞 收缩期间滑倒。 ECM还扮演着积极的功能作用 力传感器。整联蛋白是ECM的主要受体，将 细胞外基质与细胞内细胞骨架并激活信号 响应于ECM粘附的转导途径。它们对于 正常的心脏发育，心肌细胞分化和肌节 集会。整联蛋白不仅介导细胞粘附，而且还用作 生长因子的共受体刺激途径和作为机械转换器。 我们假设整联蛋白在该重要的信号调节器中起作用 心脏传感和对机械和内分泌刺激的反应 心脏止血。特别假设整联蛋白信号传导 与G蛋白偶联受体的信号通路集成的途径 （GPCR）协调调节心肌细胞的肥厚反应。 该提议的目的是定义整合素介导的作用 形态和转录变化中的粘附和信号传导 定义心肌细胞的肥厚反应途径。提议 研究将利用新生大鼠的良好表征的细胞培养模型 心室心肌细胞和腺病毒基因递送。首先，我们将确定 函数整联蛋白变体的表达或丧失功能的影响对 心肌细胞组织和肥厚标记基因表达。第二， 我们将确定FAK在整联蛋白介导的细胞变化中的作用 与心肌肥大有关。第三，我们将确定 关系的机理基础，将整合素信号传导伴 GPCR激动剂诱导的肌细胞中的肥厚反应。研究将寻求 确定GPCR介导的信号传导和 整联蛋白信号通路和整联蛋白的关键效应分子 信号表明，心脏合作调节肾上腺素能信号通路 心肌细胞。总体而言，这些研究将为分子提供见解 是补偿性肥厚的生长反应以及 过渡到心力衰竭。对心肌细胞的更了解 信号通路可能会导致适用于 在人心肌中发现的病理改变。