MYOCARDIAL INTEGRINS AND VENTRICULAR REMODELING

心肌整合素和心室重构

• 批准号: 6224519
• 负责人: Joseph S Janicki
• 金额: $ 1.55万
• 依托单位: AUBURN UNIVERSITY AT AUBURN
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-11 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6224519
• 关键词: collagen; extracellular matrix; gene expression; heart failure; heart function; histopathology; integrins; intracardiac volume; laboratory rat; metalloendopeptidases; myocardium; protein protein interaction

The heart's size, shape, and function are regulated by the dynamic interaction between components of the extracellular matrix (ECM), specific cell surface receptors (integrins), the cytoskeleton, and intrinsic genetic regulation of cellular function. We know from developmental studies that integrins are important structural elements which mediate the attachment of cardiac myocytes and fibroblasts to the ECM. In addition to their structural role, integrins mediate both chemical (i.e., cytokines and growth factors) and mechanical signal transduction which is essential in modulating cellular phenotype, intracellular signaling cascades, gene transcription, and ECM remodeling in cardiovascular development. However, virtually no studies have been performed to investigate the role of integrins in the normal or diseased adult heart. Abnormalities in the interaction between myocardial integrins and the ECM represent a common pathway that could lead to the adverse structural and functional alterations which occur secondary to chronic pressure or volume overload. The proposed studies are designed to test the hypothesis that alterations in the dynamic interaction between myocardial integrins and the ECM are responsible for the adverse ventricular remodeling resulting in the transition to heart failure. The overall objective of this proposal is to investigate the relationship between myocardial integrins, cardiomyocyte hypertrophy, and ventricular remodeling which lead to the development of heart failure. Accordingly, this proposal will use a fistula model of chronic ventricular volume overload and an aortic coarctation model of pressure overload to examine cardiac function in the intact animal and at the cellular and molecular levels. The specific aims of the proposal are 1) describe the in vivo temporal and spatial expression of specific integrins, MMPs, collagens during compensatory ventricular remodeling progressing to heart failure; 2) characterize temporal patterns of in vitro cellular function and synthesis of integrins, MMPs, and collagens in isolated cardiomyocytes and fibroblasts; and 3) determine whether perturbations in integrin expression in vitro can restore normal cellular function. These studies will utilize a variety of physiologic, morphologic, biochemical and molecular techniques to analyze the dynamic interaction between the cardiac ECM, integrins, and gene expression at critical pathophysiological stages in progressive ventricular remodeling.

心脏的大小、形状和功能都是由心脏的动态变化来调节的。 细胞外基质（ECM）组分之间的相互作用， 特异性细胞表面受体（整合素）、细胞骨架和 细胞功能的内在遗传调节。 我们知道从 发育研究表明，整合素是重要的结构元件， 其介导心肌细胞和成纤维细胞附着于 ECM。 除了它们的结构作用外，整合素还介导 化学的（即，细胞因子和生长因子）和机械信号 转导是调节细胞表型所必需的， 细胞内信号级联、基因转录和ECM重塑 在心血管发育中。 然而，几乎没有研究 进行研究整合素在正常或患病的 成人的心 在心肌细胞间的相互作用中， 整合素和ECM代表了一个共同的途径，可以导致 继发于以下疾病的不良结构和功能改变： 慢性压力或容量超负荷。 拟议的研究旨在 为了验证这个假设， 心肌整合素和ECM之间的相互作用是导致 心室重塑导致向心力衰竭转变。 本提案的总体目标是调查 心肌整合素，心肌细胞肥大， 以及心室重塑，导致心脏发育 失败 因此，本提案将使用慢性瘘管模型， 心室容量超负荷和主动脉缩窄压力模型 超负荷检查完整动物的心脏功能， 细胞和分子水平。 该提案的具体目标是 1)描述了特异性抗体在体内的时间和空间表达， 代偿性心室重构中整合素、基质金属蛋白酶、胶原 进展为心力衰竭; 2）表征 整合素、基质金属蛋白酶和胶原的体外细胞功能和合成 在分离的心肌细胞和成纤维细胞中;和3）确定是否 在体外整合素表达的扰动可以恢复正常 细胞功能 这些研究将利用各种生理， 形态学、生物化学和分子生物学技术， 心脏ECM、整合素和基因表达之间的相互作用， 进行性室性心动过速的关键病理生理阶段 重塑