ROLE OF CAVOLIN-1 IN AIRWAY 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凹在哮喘气道重塑中的作用。 这种慢性呼吸道炎症性疾病在中国估计有1500万人受到影响 美国和全球有1亿至1.5亿人。在这一高危人群中， 受试者会出现不可逆转的重塑和呼吸道阻塞。呼吸道重塑 以上皮下基底区异常大量的肌成纤维细胞为特征 与结缔组织蛋白沉积显著增加相关的膜 导致网状板增厚。白介素4(IL-4)，一种重要的Th2细胞因子 在控制过敏反应方面，也被认为是影响呼吸道反应的效应器 改建。我们最近证实，IL-4调节小窝蛋白-1的表达 (CAV-1)。Cav-1是小窝的主要结构和功能蛋白，它显著调节 转化生长因子-β抑制其信号转导过程的活性 由转化生长因子-β受体复合体启动。转化生长因子-β1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Th2细胞因子以及更多 IL-4通过调节成纤维细胞Cav-1基因转录介导小窝缺乏症 导致气道重塑中转化生长因子-β反应增强。我们将：1)评估 假设CAV1的表达减少与其表达有关 炎症标志物，更具体地说是IL-4和转化生长因子-β与呼吸道的发展 过敏原的重塑对小鼠构成了挑战。2)研究假设在Th2中 细胞因子在哮喘中的表达，IL-4调节小窝蛋白-1的表达和小窝的形成；3) 为了验证小窝蛋白-1蛋白表达减少增强转化生长因子-β的假说 效果。

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.