The objective of this SCOR proposal is to further understand the pathogenesis of pulmonary fibrosis as it relates to IPF. The central hypothesis of this proposal is that the pathogenesis of pulmonary fibrosis is due to """"""""multiple hits"""""""" that perpetuates an imbalance of over-expression of specific pro-inflammatory/proangiogenic/pro-fibrogenic mediators and impaired innate immunity, as compared to anti -inflammatory/anti angiogenic/anti-fibrogenic factors and normal host defense. This paradigm predicts that perpetuation of inflammation, angiogenesis, fibrosis, and susceptibility to recurrent infections beyond what one would expect from immunosuppression alone; ultimately results in impaired innate immunity, susceptibility to infectious disease, and perpetuation of a pro-fibrogenic environment in EPF. This predisposes the IPF patient to more multiple hits"""""""" leading to a vicious cycle of impaired pulmonary function and eventual death. The recognition of these relationships, and to what extent these responses are altered by increased susceptibility to microbes, may yield important clues to more effective prevention and treatment of this process in humans. The SCOR will utilize a multidisciplinary approach to test this central hypothesis. This expertise consists of investigators trained in Pulmonary Diseases, Radiology, Pathology, Cell and Molecular Biology, and Biostatistics. The strengths of this proposal are the investigators, who have productive and collaborative interests in mechanisms related to pulmonary fibrosis. The exceptional institutional resources for biomedical research, the proven commitment to collaborative interaction by both clinicians and basic scientists, and the access to a large population of IPF patients will assure that the studies designed in this proposal will come to fruition.
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