CAVEOLIN-1 IN CARDIAC REMODELING

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 本研究的目的是确定小窝在心肌梗死后心肌重构中的作用。在心脏纤维化中，纤维组织取代了健康的收缩组织。增加的纤维组织还降低毛细血管密度并增加氧气必须扩散的距离，导致肌细胞缺氧，功能障碍，心律失常，并最终被非收缩性成纤维细胞取代。这些过程的调节在很大程度上由转化生长因子TGF-β控制。更好地了解心脏重塑中TGF-β信号通路的调节可能会改善心肌梗死并发症的治疗或预防。我们最近发现，减少小窝蛋白-1（cav 1）的表达导致气道重塑中TGF-β信号的增强。Cav 1通过阻止由TGF-β受体复合物引发的信号转导或增强TGF-β受体复合物的降解来调节TGF-β活性。因此，我们假设心肌梗死后的炎症反应通过cav 1依赖性机制促进TGF-β信号传导，从而促进心脏重塑。本提案的具体目的是：1）确定心肌梗死后心肌炎症是否降低cav 1表达。我们推测，心肌梗死后心肌炎症中表达的细胞因子下调cav 1的表达，导致TGF-β信号增强。我们将比较野生型小鼠梗死和非梗死组织中cav 1的表达，并研究TGF-β信号的激活。2)阐明IL-6调节TGF-β受体区室化从而促进TGF-β信号传导的机制。我们假设IL-6促进TGF-β受体分配到非cav 1囊泡中，因此减少TGF-β受体周转并促进信号传导。3)确定cav 1基因切除如何调节TGF-β信号传导。我们推测cav 1缺陷增强了心肌重塑中TGF-β的作用。我们将比较野生型和cav 1缺陷小鼠梗死组织中TGF-β对Smad信号传导的激活。我们还将确定潜在的新的监管机制，是cav 1的独立。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The objective of this study is to determine the role of caveolae in myocardial remodeling after myocardial infarction. In cardiac fibrosis, fibrous tissue replaces healthy contractile tissue. Increased fibrous tissue also decreases capillary density and increases the distance oxygen must diffuse, leading to hypoxia of myocytes with dysfunction, dysrhythmia, and eventual replacement by non-contractile fibroblasts. The regulation of these processes is controlled in large part by transforming growth factor TGF-beta. A better understanding of the regulation of the TGF-beta signaling pathway in cardiac remodeling could lead to improved treatment or prevention of this complication of myocardial infarction. We recently demonstrated that reduced expression of caveolin-1 (cav1) leads to enhanced TGF-beta signaling in airway remodeling. Cav1 regulates TGF-beta activity by either preventing signal transduction initiated by the TGF-beta receptors complex or enhancing the degradation of the TGF-beta receptors complex. We therefore hypothesize that the inflammatory response following myocardial infarction contributes to cardiac remodeling by promoting TGF-beta signaling via a cav1-dependent mechanism. The specific aims of this proposal are:1) Determine whether myocardial inflammation decreases cav1 expression after myocardial infarction. We hypothesize that cytokines expressed in myocardial inflammation following infarct downregulates cav1 expression leading to TGF-beta signaling enhancement. We will compare cav1 expression in wild type mice in infarcted and non-infarcted tissue and examine the activation of TGF-beta signaling. 2) Explicate the mechanism by which IL-6 regulates the compartmentalization of TGF-beta receptors and thereby promotes TGF-beta signaling. We hypothesize that IL-6 promotes the partitioning of TGF-beta receptors into non-cav1 vesicles and therefore reduced TGF beta receptor turnover and promoting signaling. 3) Determine how genetic ablation of cav1 modulates TGF-beta signaling. We hypothesize that cav1-deficiency enhances TGF-beta effects in myocardial remodeling. We will compare the TGF-beta activation of Smad signaling in infarcted tissues in wild type and cav1-deficient mice. We will also identify potential new regulatory mechanisms that are cav1-independent.