Integrin Function in Cardiac Remodeling

描述（由申请人提供）：整合素是粘附受体和信号分子。它们在心脏中的作用知之甚少。21整联蛋白是在心肌细胞和成纤维细胞中表达的主要2整联蛋白亚基，并且在这些细胞类型中的每一种中与几个1亚基配对。目前建议的总体假设是，心肌细胞和成纤维细胞整合素是心脏内信号传导和结构的关键组织者。这些细胞受体的功能的知识将使我们能够建立一个更好的理解心脏重塑后的血流动力学或缺血性压力。利用独特的小鼠模型和来源于它们的细胞，该提议将集中于三个目标：1）确定心肌细胞中整合素和G蛋白偶联受体途径之间的缺陷性机械信号传导和信号串扰调节的机制：集中于小窝和粘着斑蛋白。心肌细胞中21整合素表达的减少导致压力负荷心脏和异丙肾上腺素刺激的分离心肌细胞下游信号的改变。我们将测试的假设，减少肌细胞整合素可以改变机械和肾上腺素能信号通过干扰多个亚细胞信号的整合-如局灶性粘连和小窝，并干扰下游信号可能发生通过局灶性粘连激酶依赖和独立的途径。2)探讨心肌细胞整合素在短期缺血/再灌注及心肌梗死后的作用。肌细胞表面上21种整合素的减少导致经受缺血/再灌注的心脏的异常功能反应，而肌细胞上整合素的过表达提供缺血保护。为此，将使用基因操作的小鼠模型评价将整联蛋白表达水平与心肌缺血性功能障碍/保护联系起来的机制，其中肌细胞整联蛋白减少或过表达。这里的工作将与aim 3中的心脏成纤维细胞的研究联系起来。我们假设整合素异二聚体改变膜稳定性或肌细胞信号传导，从而改变心脏对缺血或梗死的反应。3)评估21整合素在心脏纤维化和成纤维细胞功能中的作用：在鼠心脏中发生纤维化，其中21整合素的肌细胞表达减少。这一目标将确定导致这种表型的机制，特别是在病理性心脏（例如心肌梗死后）中，并研究肌细胞：成纤维细胞的相互作用。这里要测试的假设是肌细胞上整联蛋白表达的改变导致对成纤维细胞的旁分泌效应，并且成纤维细胞上整联蛋白表达水平的改变将在功能上影响成纤维细胞和潜在的成纤维细胞-肌成纤维细胞转化。

DESCRIPTION (provided by applicant): Integrins are adhesive receptors and signaling molecules. Their role in the heart is poorly understood. 21 integrin is the dominant 2 integrin subunit expressed in cardiac myocytes and fibroblasts and partners with several 1 subunits in each of these cell types. The overall hypothesis of the current proposal is that cardiac myocyte and fibroblast integrins are critical organizers of signaling and structure within the heart. Knowledge of the function of these cellular receptors will allow us to establish a greater understanding of how the heart remodels following hemodynamic or ischemic stresses. Using unique mouse models and cells derived from them, this proposal will focus on three aims: 1) To determine the mechanism(s) for defective mechanical signaling and modulation of signaling crosstalk between integrin and G-protein coupled receptor pathways in the cardiac myocyte: focus on caveolae and focal adhesion proteins. Reduced 21 integrin expression in the cardiac myocyte leads to alterations in downstream signaling in heart subjected to pressure loading and in isolated myocytes stimulated with isoproterenol. We will test the hypothesis that reduction of myocyte integrins can alter mechanical and adrenergic signaling by disturbing multiple sub-cellular signaling integrators - e.g. focal adhesions and caveolae, and that disturbed downstream signaling may occur through both focal adhesion kinase dependent and independent pathways. 2) To evaluate the role of myocyte integrins in short-term ischemia / reperfusion and following myocardial infarction. Reduction of 21 integrins on the myocyte cell surface leads to abnormal functional responses of the heart subjected to ischemia / reperfusion while overexpression of integrins on the myocyte offers ischemic protection. In this aim the mechanism(s) which links integrin expression levels to myocardial ischemic dysfunction / protection will be evaluated using genetically manipulated mouse models where myocyte integrins are reduced or overexpressed. Work here will tie to studies of cardiac fibroblasts in aim 3. We hypothesize that integrin heterodimers modify membrane stability or myocyte signaling which alters responses of the heart to ischemia or infarction. 3) To assess the role of 21 integrins in cardiac fibrosis and fibroblast function: Fibrosis occurs in the murine heart with reduced myocyte expression of 21 integrin. This aim will determine the mechanism(s) which lead to this phenotype, particularly in the pathological heart (e.g. post-myocardial infarction) and study myocyte: fibroblast interactions. The hypotheses to be tested here will be that alteration of integrin expression on the myocyte leads to paracrine effects on the fibroblast and that altered 21 integrin expression levels on the fibroblast will functionally affect the fibroblast and potentially fibroblast- myofibroblast conversion.