This proposal, which is an application for continuation of this Program Project, presents a multidisciplinary program comprised of four projects and three cores designed to investigate epithelial-derived matrix molecules and proteases, host defense molecules, and immune effector cells in the context of lung injuries induced by viruses and inhaled toxins. Focal points of the proposed studies will be laminin-332 (laminin-5), surfactant protein D (SP-D), matrilysin (MMP-7), serglycin, and a distinct population of non-B non-T (NBNT) lymphoid cells. Major hypotheses are that: (1) laminin-332 plays key roles in responses to alveolar and airway injury via its effects on epithelial cells;(2) SP-D contributes to the airway defense against RNA viruses and that alterations in SP-D expression contribute to post-viral airway remodeling;(3) interactions between the chondroitin sulfate E chains of serglycin and pro-matrilysin constitute an important pathway for matrilysin activation;and (4) a distinct NBNT lymphoid cell population is involved in mucous cell metaplasia following respiratory viral infections. The proposed studies combine murine models of airway and alveolar injury induced by Sendai virus, cigarette smoke and naphthalene with state-of-the art epithelial culture systems, transgenic and gene targeted mice, genetic and glycomic array technologies, and crystallographic analysis. A Morphology Core / Cell Culture Core for assistance with morphologic procedures and for isolation and maintenance of respiratory epithelial cells, and a Mouse Core for production of transgenic and targeted mice and for implementing models of cigarette smoke-induced lung injury and respiratory viral infections, will be specialized centers for the investigators in their complementary, yet independent, studies. This application builds on a long history of productive research and collaboration related to mechanisms of lung remodeling and the response to pulmonary injury.
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