METALLOELASTASE INDUCTION FOLLOWING INTEGRIN KNOCKOUT

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DESCRIPTION (Adapted from applicant?s abstract) Dr. David Morris is a pulmonary and critical care physician with a strong commitment to an academic career as an independent investigator in respiratory cellular and molecular biology. His particular interest is lung remodeling. Through work in the Lung Biology Center at UCSF/SFGH he has identified a novel animal model of bronchitis and emphysema resulting from inactivation of an epithelial integrin (alpha2- beta6). He is proposing a program of advanced research training consisting of independent experimental studies mentored by an expert in integrin biology (Dr. Dean Sheppard); a research advisory committee including experts on matrix metalloproteinases (Dr. Zena Werb), protease biology (Dr. Caughey), and pulmonary immunology (Dr. Erle); and a formal didactic program including courses in biochemistry, cell biology, and immunology. His research program will address the hypothesis that the integrin alpha2-beta6 on the surface of respiratory epithelial cells modulates alveolar macrophage expression of Macrophage Metalloelastase (MME, MMP-12) thereby regulating airway inflammation, and matrix degradation. He will address this hypothesis through three specific aims. First, he will determine which regions of the beta6 integrin subunit are critical to prevent persistent MMP-12 (MME) overexpression by alveolar macrophages and avert the development of emphysema in beta6 -/- mice using novel transgenic lines. Second, he will determine the role of MMP-12 (MME) upregulation in the recruitment and activation of macrophages and lymphocytes in beta6 -/- mice using double knockout mice. Finally, he will determine the role of Transforming Growth Factor Beta1, and of alpha2-beta6 mediated activation of latent TGFbeta1 in the regulation of airway inflammation and MMP-12 (MME) expression in vivo using both adenovector gene transfer and transgenic approaches. This work promises to yield important insights into the fundamental biology underlying both chronic airway inflammation and emphysema. Dr. Morris will complete this work in the Lung Biology Center (LBC), internationally recognized research center with an outstanding record of training independent academic pulmonary scientists. The Department of Medicine and LBC are fully committed to Dr. Morris? career development and to making all necessary resources available to facilitate successful completion of this work.