Mfge8 and the Role of Apoptotic Cell Clearance in Lung Injury

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This proposal outlines a five-year career development program designed to prepare Dr. Atabai for a career as an academic physician-scientist in pulmonary medicine. Dr. Atabai is interested in studying the mechanisms underlying injury and repair, particularly as they relate to the lung. Acute Lung Injury (All) is a common and devastating inflammatory condition that can lead to pulmonary fibrosis. Despite high mortality rates few effective therapies exist for ALL Recent evidence has implicated a pathogenic role for apoptosis in human ALI and pulmonary fibrosis. Under the guidance of his mentor, Dr. Dean Sheppard, Dr. Atabai has been examining the role of MfgeS, an integrin binding molecule that facilitates apoptotic cell engulfment, in lung injury. Dr. Atabai has found that mice lacking functional MfgeS develop exaggerated pulmonary fibrosis after intratracheal bleomycin administration. Bleomycin induces epithelial cell apoptosis, inflammation and pulmonary fibrosis. Dr. Atabai's hypothesis is that MfgeS modulates injury and inflammation in the lung by facilitating apoptotic cell clearance. The specific aims designed to test this hypothesis are 1) determining the role of MfgeS in apoptotic cell clearance in the lung, 2) determining the role of MfgeS in regulating inflammation and the severity of lung injury, 3) determining the role of phosphatidylserine residues on apoptotic cells and the avps and av(35 integrins on phagocytes in MfgeS-mediated apoptotic cell clearance in vivo. Dr. Atabai will use well-established in vitro and in vivo techniques to achieve these aims including cell culture, generation of recombinant proteins, immunohistochemistry, immunocytochemistry, DNA expression arrays, Real-Time PCR, ELISA, and immunoblotting. Dr. Atabai's mentor, Dr. Dean Sheppard, is a productive and well-funded scientist with expertise in integrin biology and inflammation and fibrosis in the lung. Dr. Sheppard has an outstanding track record of training successful academic physicians. An advisory panel of highly regarded scientists will provide further guidance to Dr. Atabai for the duration of the award. A detailed program of didactic course training and participation in local and national scientific conferenceswill be the final component of the program. Dr. Atabai has the full commitment of the UCSF Department of Medicine and the Lung Biology Center with regard to career development and access to all the resources necessary for the successful completion of this work.