Role of Integrins in Cardiac Myocyte Function

整合素在心肌细胞功能中的作用

• 批准号: 6364183
• 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/6364183
• 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）是一种 心脏力学的重要决定因素。它通过以下方式发挥结构作用 维持肌细胞和血管的排列并防止肌细胞 收缩时的滑移。 ECM 还发挥着积极的功能作用 力传感器。整合素是 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 ECM 粘附的转导途径。它们对于 正常心脏发育、心肌细胞分化和肌节 集会。整合素不仅介导细胞粘附，而且还充当 生长因子刺激途径的共受体和作为机械传感器。 我们假设整合素在 心脏对机械和内分泌刺激进行感知和响应以维持 心脏止血。特别假设整合素信号传导 通路与 G 蛋白偶联受体的信号通路整合 (GPCR) 协调调节心肌细胞的肥大反应。 该提案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 定义心肌细胞肥大反应途径。拟议的 研究将利用新生大鼠的特征明确的细胞培养模型 心室肌细胞和腺病毒基因传递。首先，我们将确定 功能整合素变体的表达的影响 心肌细胞组织和肥大标记基因表达。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 整合素信号耦合关系的机制基础 GPCR 激动剂诱导的肌细胞肥大反应。研究将寻求 确定 GPCR 介导的信号传导和 整合素信号通路和整合素的关键效应分子 协同调节心脏中肾上腺素能信号通路的信号传导 肌细胞。总的来说，这些研究将为分子生物学提供深入的见解。 代偿性肥大生长反应的基础途径以及 向心力衰竭的转变。对心肌细胞有更深入的了解 信号通路可能会带来新的治疗方法 在人类心肌中发现的病理改变。