ROLE OF CAVOLIN-1 IN AIRWAY REMODELING

这个子项目是许多研究子项目中的一个 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来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 本研究的目的是确定小窝在哮喘气道重塑中的作用。 这种呼吸道慢性炎症性疾病影响着世界上大约1500万人， 美国和全世界1亿至1.5亿人。在这些高危人群中， 受试者将发生不可逆的重塑和气道阻塞。气道重塑是 其特征在于上皮下基底中异常大量的肌成纤维细胞 与结缔组织蛋白沉积显著增加相关的膜 导致网状层增厚。白细胞介素4（IL-4），一种重要的Th 2细胞因子 在过敏反应的控制中，也被认为是影响气道的效应物 重塑我们最近证实IL-4调节小窝蛋白-1的表达， （cav-1）。Cav-1是细胞膜小窝的主要结构和功能蛋白， 转化生长因子（TGF）-β活性通过抑制其转导信号过程 由TGF-β受体复合物引发。TGF-β 1是一种关键的促纤维化细胞因子， 哮喘和纤维化因此，我们的目标是证明Th 2细胞因子等 特别是IL-4通过调节成纤维细胞中cav-1基因转录介导小窝缺陷 导致气道重塑中TGF-β反应增强。我们将：1）评估 假设cav 1的表达减少与 炎症标志物，更具体地说是IL-4和TGF-β，以及气道的发展 在过敏原激发的小鼠中重塑。2)研究假设，在Th 2 哮喘中表达的细胞因子，IL-4调节小窝蛋白-1表达和小窝形成; 3） 为了验证小凹蛋白-1蛋白表达的减少增强TGF-β的假设， 方面的影响.

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 airway remodeling in asthma. This chronic inflammatory disease of the airways affects an estimated 15 million people in the United States and 100-150 million people worldwide. Among this population at risk, a subset of subjects will develop irreversible remodeling and airway obstruction. Airway remodeling is characterized by an abnormally large number of myofibroblasts in the subepithelial basement membrane associated with significantly increased deposition of connective tissue proteins leading to a thickening of the lamina reticularis. Interleukin 4 (IL-4), a Th2 cytokine important in the control of allergic response, has also been proposed as an effector influencing airway remodeling. We have recently demonstrated that IL-4 regulates the expression of caveolin-1 (cav-1). Cav-1, main structural and functional protein of caveolae, notably regulates transforming growth factor (TGF)-beta activity by dampening its transduction signal process initiated by the TGF-beta receptor complex. TGF-beta1 is a pivotal pro-fibrotic cytokine in asthma and fibrosis. Our goal, therefore, is to demonstrate that Th2 cytokines, and more specifically IL-4, mediate caveolae deficiency by regulating cav-1 gene transcription in fibroblasts resulting in enhanced TGF-beta responses in airway remodeling. We will: 1) Evaluate the hypothesis that the reduced expression of cav1 is associated with the expression of inflammatory markers, more specifically IL-4 and TGF-beta, and the development of airway remodeling in allergen challenged mice. 2) Investigate the hypothesis that among the Th2 cytokines expressed in asthma, IL-4 regulates caveolin-1 expression and caveolae formation; 3) To test the hypothesis that the reduced expression of caveolin-1 protein enhances TGF-beta effects.