Role of Integrins in Cardiac Myocytes

性状（由申请人提供）：整合素，异二聚体跨膜 连接细胞外基质分子和细胞骨架蛋白的受体， 信号复合物，在正常的心脏发育，心肌细胞 分化和维持肌节组织。诱导的突变 证明了整合素及其配体在 维持心肌功能。整合素不仅介导细胞 粘附，但也作为拉伸受体和生长因子的辅助受体 刺激的路径。我们假设整合素的功能是重要的 心脏中的调节剂，感知和响应机械和内分泌 维持体内平衡的刺激。我们使用体外模型和体内模型， 表达式来开始这个假设。体外研究表明， 需要整合素连接到细胞外基质和整合素信号传导 心肌细胞对通过G蛋白起作用的肥大激动剂的反应 偶联受体补充的体内研究表明， 在整联蛋白α 5亚基中表达功能获得突变，或 表达干扰整联蛋白功能的嵌合蛋白导致 严重的，围产期致死表型的转基因小鼠 利用综合方法进一步剖析整合素在 心肌细胞的结构和功能。近端介质的作用 整合素信号在心肌细胞肥大反应中的作用将是 用培养的肌细胞的体外模型系统评价。的重要性 将在体外系统中鉴定候选整合素效应物 通过在转基因植物中过表达这些候选基因来验证或反驳 动物一个完善的条件性转基因表达系统将决定转基因的表达。 转基因表达在成年心脏中的作用。心脏表型导致 从转基因表达将与形态和分子 在体外肌细胞中观察到的改变。最后，生理 将通过确定转基因表达的影响来检查转基因表达的相关性。 转基因表达对基础条件下和 血流动力学负荷这些研究将为研究心肌细胞 信号通路和方法适用于病理改变， 人体心肌

DESCRIPTION (provided by applicant): Integrins, heterodimeric transmembrane receptors linking extracellular matrix molecules with cytoskeletal proteins and signaling complexes, are essential in normal cardiac development, cardiomyocyte differentiation, and maintenance of sarcomere organization. Induced mutations in mice demonstrate the importance of integrins and their ligands in maintenance of cardiac muscle function. Integrins not only mediate cell adhesion, but also serve as stretch receptors and co-receptors in growth factor stimulated pathways. We hypothesize that integrins function as important modulators in the heart, sensing and responding to mechanical and endocrine stimuli to maintain homeostasis. We have used in vitro models and in vivo expression to begin to this hypotheses. In vitro studies demonstrate that integrin ligation to extracellular matrix and integrin signaling is required for cardiomyocytes to respond to hypertrophic agonists acting via G-protein coupled receptors. Complementary in vivo studies demonstrate that transgenic expression of a gain of function mutation in the integrin a5 subunit, or expressing a chimeric protein interfering with integrin function results in a severe, perinatal lethal phenotype in transgenic mice The proposed studies will utilize an integrated approach to further dissect the role of integrins in the structure and function of cardiac myocytes. The role of proximal mediators of integrin signaling in the hypertrophic response of cardiac myocytes will be evaluated with an in vitro model system of cultured myocytes. The importance of candidate integrin effectors identified in the in vitro system will be validated or refuted by overexpressing these candidate genes in transgenic animals. A refined conditional transgene expression system will determine the effect of transgene expression in the adult heart. Cardiac phenotypes resulting from transgene expression will be correlated with morphological and molecular alterations observed in myocytes in vitro. Finally, the physiological correlates of transgene expression will be examined by determining the effect of transgene expression on cardiac function under basal conditions and after hemodynamic loading. These studies will provide new insights into myocyte signaling pathways and approaches applicable to pathologic alterations in the human myocardium.