A 5 year training program for the development of a career in academic pulmonary is outlined in this proposal. The principal investigator (PI) has completed residency in internal medicine at the University of Chicago followed by a fellowship in pulmonary and critical care medicine at the University of Chicago. He is now an Instructor in the Section of Pulmonary and Critical Care, University of Chicago (effective July 1, 2008). He will expand upon his scientific skills through a unique program of training in cellular signaling. This program will promote command of the application of cellular signaling to the study of basic mechanisms of fibrotic human diseases, such as pulmonary fibrosis and bronchiolitis obliterans. Dr. Nickolai Dulin will mentor the principal investigator's scientific development. He is a well-established investigator in cell signaling and an outstanding mentor who is committed to the development of the PI into an independent clinician-scientist. Dr. Julian Solway, an outstanding physician-investigator who has successfully trained many clinician-scientists will serve as the Co-Mentor. He will provide expertise in academic and scientific career development. In addition, an advisory committee of accomplished scientists in cellular signaling, pulmonary physiology, and molecular biology will contribute to the scientific and career development. The research focus will be on the role of serum response factor (SRF) in mediating myofibroblast differentiation in the setting of pulmonary fibrosis. The Pis preliminary data shows that 1) SRF is required for myofibroblast differentiation induced by the profibrotic cytokine, TGF-beta, 2) that activators of PKA inhibits myofibroblast differentiation likely via inhibition of SRF, and 3) the stable prostacyclin agonist, iloprost, attenuates the development of pulmonary fibrosis in a murine model. Thus, the overall hypothesis is that TGF-beta stimulates myofibroblast differentiation through activation of serum response factor, and that TGF- beta-induced myofibroblast differentiation can be inhibited by targeting SRF activity both in cell culture and in vivo.
My long-term objective is to understand the molecular mechanisms underlying the pathogenesis of pulmonary fibrosis, focusing on myofibroblast differentiation. Identification of these signaling pathways may lead to the development of new drug treatments for this progressive, fatal disease.
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