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.
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