Role of Integrins in Cardiac Myocytes

描述(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 信号复合体，是正常心脏发育所必需的，心肌细胞 肌节组织的分化和维持。诱变 在小鼠身上展示了整合素及其配体在 维持心肌功能。整合素不仅介导细胞 黏附，但也作为伸展受体和生长因子的辅助受体 刺激的通路。我们假设整合素的作用 心脏中的调节器，对机械和内分泌的感知和反应 维持体内平衡的刺激物。我们已经使用了体外模型和体内模型 表达开始于这一假设。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转导 心肌细胞对通过G蛋白作用的肥大激动剂的反应 偶联受体。体内互补研究表明，转基因 整合素a5亚基中功能突变增益的表达，或 表达干扰整合素功能的嵌合蛋白会导致 转基因小鼠严重的围产期致命表型拟议的研究将 利用一种综合的方法来进一步剖析整合素在 心肌细胞的结构和功能。近端中介物的作用 整合素信号在心肌细胞肥大反应中的作用 用体外培养的心肌细胞模型系统进行评价。重要的是 在体外系统中确定的候选整合素效应器将是 通过在转基因中过度表达这些候选基因来证实或驳斥 动物。一个完善的条件转基因表达系统将决定 转基因在成人心脏中表达的影响。导致的心脏表型 来自转基因的表达将与形态和分子相关 在体外观察到的心肌细胞的变化。最后，生理学的 转基因表达的相关性将通过确定影响 基础状态下和基础状态下转基因表达对心功能的影响 血流动力学负荷。这些研究将为研究心肌细胞提供新的见解。 适用于脑血管病变的信号通路和途径 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.