Integrin Regulation of Airway Epithelial Proliferation

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DESCRIPTION (provided by applicant): The goal of this application is to establish an independent research program investigating the mechanisms regulation of airway epithelial proliferation. Through gaining mechanistic insight, the long-term goal of this work is to identify novel molecular targets to advance the therapeutic and diagnostic approaches for neoplastic and inflammatory diseases of the human airway. The candidate is a recently appointed assistant professor of pathology currently engaged in a 40 percent research and 60 percent clinical/teaching effort. His clinical expertise is in general and pulmonary pathology. The impetus for the K02 award is to provide salary to allow for an intensive research focus. Thus, as this application proposes, the candidate's institutional effort would be reallocated to 75 percent research and 25 percent clinical/teaching. The Department of Pathology is in complete support of the candidate and for this time reallocation. The candidate currently occupies 750 sq. ft of independent, fully outfitted, dedicated research space. Through affiliation with the Lung Biology Research Program at San Francisco General Hospital and the UCSF/Mt. Zion Cancer Center, the academic environment is ideal for career advancement. The research proposed is an extension of a recently funded research grant application (HL63993-01), which seeks to elucidate the mechanisms of integrin alpha v beta 8mediated inhibition of airway epithelial cell growth. The purpose of the current proposal is to place the mechanistic insights gained into biologic context using a novel biologically relevant model. This will be accomplished by addressing the following hypothesis in three specific aims: Hypothesis: In intact human airway, integrins mediate epithelial homeostasis through cell-extracellular-matrix interactions and through direct interactions with growth factors/cytokines. Specific Aim 1: To establish a valid biologic model to study human airway proliferation. Specific Aim 2: To test the role of integrins in the regulation epithelial cell growth in a biologically relevant model of the human airway. Specific Aim 3: To test the mechanism of integrin-mediated regulation of cell proliferation in a biologically relevant model of the human airway.