CAVEOLIN-1 IN CARDIAC REMODELING

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 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。纤维组织的增加还会降低毛细血管密度，增加氧气扩散的距离，导致心肌细胞缺氧并伴有功能障碍、心律失常，最终被非收缩成纤维细胞取代。这些过程的调节在很大程度上是由转化生长因子转化生长因子β控制的。更好地了解转化生长因子-β信号通路在心脏重构中的调节可能有助于改善心肌梗死这一并发症的治疗或预防。我们最近证实，小窝蛋白-1(CAV1)的表达减少导致了转化生长因子-β信号在气道重塑中的增强。Cav1通过阻止由转化生长因子-β受体复合体启动的信号转导或促进转化生长因子-β受体复合体的降解来调节转化生长因子-β活性。因此，我们假设，心肌梗死后的炎症反应通过促进转化生长因子-β信号转导而促进心脏重塑，其机制依赖于血管腔蛋白1。这一建议的具体目的是：1)确定心肌梗死后心肌炎症是否降低了CAM1的表达。我们假设，在心肌梗死后炎症中表达的细胞因子下调了CAV1的表达，从而导致转化生长因子-β信号增强。我们将比较野生型小鼠在梗死和非梗死组织中的表达，并检测转化生长因子-β信号的激活。2)阐明IL-6调节转化生长因子-β受体的区域化，从而促进转化生长因子-β信号转导的机制。我们假设IL-6促进了转化生长因子-β受体在非血管腔小泡中的分配，从而减少了转化生长因子-β受体的周转，促进了信号转导。3)确定CAV1基因消融对转化生长因子-β信号转导的影响。我们假设CAV1缺乏可增强心肌重塑中的转化生长因子-β效应。我们将比较野生型和CAV1缺陷小鼠脑梗塞组织中Smad信号的转化生长因子-β激活情况。我们还将确定潜在的新的调控机制，这些机制不依赖于CAP1。

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.