Integrin Function in Cardiac Remodeling

点击翻译按钮获取中文摘要

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.