This application requests funds to continue multi-disciplinary studies of cellular and molecular mechanisms of airway remodeling of chronic inflammation. Drs. Basbaum, Caughey, and McDonald have collaborated closely in this Program Project Grant for may years and now, with the addition of Dr. Killeen, and experienced immunologist, will direct their efforts to the cellular and molecular pathophysiology of chronic inflammation of the airways. The investigators will focus on the mechanisms and consequences of the influx of inflammatory cells and changes in the epithelium, vasculature, and connective tissue matrix that result in airway remodeling. Using state-of-the-art molecular, cellular, morphological, immunological, and transgenic approaches, the Program Project team will approach the problem in four ways. Project 1, led by Dr. Basbaum, will explore the roles of recruited leukocytes in regulating epithelial hyperplasia, metaplasia, and mucin gene expression. The project, led by Dr. Caughey, will investigate roles of proteases from mast cells and other airway cells in regulating microvascular, epithelial, and matrix remodeling. The project led by Dr. Killeen, will examine roles of lymphocytes and novel TNF-family receptors in the remodeling of the airway microvasculature and epithelium. The project led by Dr. McDonald, will examine the mechanisms and consequences of microvascular remodeling in chronic airway inflammation and will explore the use of angiostatic drugs to reverse the remodeling Mycoplasma pulmonis infection in normal and genetically altered mice will be used in many of the studies is a model for studying chronic airway inflammation. The Program Project team has a long tradition of collaborative research and the use of multi-disciplinary strategies for studying airway inflammation. Collectively, they have a powerful armory of skills in cellular and molecular biology, enzymology, microscopy, immunology, and organ physiology to solve the mysteries of airway remodeling in chronic disease. Understanding the causes of remodeling will suggest novel strategies to prevent or reverse the long lasting changes in the airway wall typical of asthma bronchitis, cystic fibrosis, and other chronic inflammatory diseases, which affect a growing share of the population.
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