This application requests funding to continue complementary, multidisciplinary studies of mechanisms of airway and lung remodeling in chronic inflammation. Drs. Caughey, McDonald, Baluk and Krummel collaborated closely to reveal important roles played by immune cells, peptidases, and growth factors in the pathophysiology of remodeling. Insights from the studies, including once unsuspected roles for lymphatic vessels, mast cells, lymphocytes and dendritic cells, suggest new paradigms for understanding evolution of structural changes in mucosal microenvironments in inflamed ain/vays, with implications for causes and treatment of chronic disease. Going fooA^ard, the team will use biochemical, cellular and physiological approaches, including real time two-photon imaging, to define the triggers, consequences and reversibility of remodeling, emphasizing factors governing resolution. Project 1, led by Dr. Caughey, will use pharmacoenzymatic and genetic tools to explore roles of airway peptidases in remodeling and host defense, focusing on mast cell and epithelial transmembrane peptidase contributions to resolution of inflammation and defense against mycoplasma. Project 2, led by Dr Krummel, will use novel two-photon live imaging of reporter mice to identify sites, nature and importance of interactions between T-cells, antigen-presenting cells, mast cells and lymphatics as ainway microenvironments evolve and remodel in inflammation. Project 3, led by Dr. McDonald, will use conditional mutant mice and novel inhibitors to determine cellular mechanisms, consequences and reversibility of lymphangiogenesis and angiogenesis in sustained airway inflammation. Here, emphasis will be on cellular actions of factors that drive proliferation and remodeling of lymphatics and blood vessels, and exploitation of findings that lymphatic and blood vessel remodeling are mechanistically, temporally and functionally distinct. Each of the projects benefits from a scientific core led by Drs. Krummel and Baluk to facilitate mycoplasmal infection, mouse genotyping, and live cell imaging. These plans will ensure that the Program's tradition of collaborative research on molecular and cellular mechanisms of airway inflammation and remodeling will continue to yield insights of basic and translational importance.
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