CAVEOLIN-1 IN CARDIAC REMODELING

CAVEOLIN-1 在心脏重构中的作用

• 批准号: 7959641
• 负责人: Claude Le Saux
• 金额: $ 21.92万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959641
• 关键词: Ablation; Blood capillaries; Cardiac; Cardiovascular system; Caveolae; Centers of Research Excellence; Complex; Complication; Computer Retrieval of Information on Scientific Projects Database; Diffuse; Fibroblasts; Fibrosis; Functional disorder; Funding; Genetic; Grant; Hypoxia; Infarction; Inflammation; Inflammatory Response; Institution; Interleukin-6; Lead; Mus; Muscle Cells; Myocardial; Myocardial Infarction; Oxygen; Prevention; Process; Regulation; Research; Research Personnel; Resources; Role; Signal Transduction; Source; TGF Beta Signaling Pathway; Tissues; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Transforming Growth Factors; United States National Institutes of Health; Ventricular Remodeling; Vesicle; Wild Type Mouse; airway remodeling; capillary; caveolin 1; cytokine; density; improved; prevent

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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 这项研究的目的是确定小窝在心肌梗塞后心肌重塑中的作用。 在心脏纤维化中，纤维组织取代了健康的收缩组织。 增加的纤维组织还会降低毛细血管密度，并增加距离氧的氧气必须扩散，从而导致肌细胞缺氧，功能障碍，功能障碍和最终被非收缩成纤维细胞替换。这些过程的调节在很大程度上是通过转化生长因子TGF-beta来控制的。更好地了解心脏重塑中TGF-β信号通路的调节可能会改善治疗或预防这种心肌梗塞并发症。 我们最近证明，小窝蛋白-1（CAV1）的表达降低会导致气道重塑中TGF-β信号的增强。 CAV1通过防止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，我们假设心肌梗塞后的炎症反应通过通过CAV1依赖机制促进TGF-β信号传导来促进心脏重塑。该提案的具体目的是：1）确定心肌炎症后心肌炎症是否会降低心肌梗塞后CAV1的表达。 我们假设梗塞后在心肌炎症中表达的细胞因子下调CAV1表达导致TGF-β信号的增强。 我们将比较梗塞和非刻张组织中野生型小鼠中的CAV1表达，并检查TGF-β信号传导的激活。 2）解释IL-6调节TGF-beta受体的隔室的机制，从而促进TGF-β信号传导。我们假设IL-6促进了TGF-β受体在非CAV1囊泡中的分配，因此降低了TGF-β受体转换和促进信号传导。 3）确定CAV1的遗传消融如何调节TGF-β信号传导。 我们假设CAV1缺陷可以增强心肌重塑中的TGF-β效应。 我们将比较野生型和CAV1缺陷小鼠中梗塞组织中SMAD信号传导的TGF-β激活。我们还将确定与CAV1无关的潜在新调节机制。