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.
|Bernau, Ksenija; Torr, Elizabeth E; Evans, Michael D et al. (2017) Tensin 1 Is Essential for Myofibroblast Differentiation and Extracellular Matrix Formation. Am J Respir Cell Mol Biol 56:465-476|
|Esnault, Stephane; Bernau, Ksenija; Torr, Elizabeth E et al. (2017) RNA-sequencing analysis of lung primary fibroblast response to eosinophil-degranulation products predicts downstream effects on inflammation, tissue remodeling and lipid metabolism. Respir Res 18:188|
|Ferguson, Keith T; Torr, Elizabeth E; Bernau, Ksenija et al. (2017) The Novel mTOR Complex 1/2 Inhibitor P529 Inhibits Human Lung Myofibroblast Differentiation. J Cell Biochem 118:2241-2249|
|Annis, Douglas S; Ma, Hanqing; Balas, Danika M et al. (2015) Absence of Vitamin K-Dependent ?-Carboxylation in Human Periostin Extracted from Fibrotic Lung or Secreted from a Cell Line Engineered to Optimize ?-Carboxylation. PLoS One 10:e0135374|
|Torr, Elizabeth E; Ngam, Caitlyn R; Bernau, Ksenija et al. (2015) Myofibroblasts exhibit enhanced fibronectin assembly that is intrinsic to their contractile phenotype. J Biol Chem 290:6951-61|
|Bernau, Ksenija; Ngam, Caitlyn; Torr, Elizabeth E et al. (2015) Megakaryoblastic leukemia-1 is required for the development of bleomycin-induced pulmonary fibrosis. Respir Res 16:45|
|Tilbury, Karissa; Hocker, James; Wen, Bruce L et al. (2014) Second harmonic generation microscopy analysis of extracellular matrix changes in human idiopathic pulmonary fibrosis. J Biomed Opt 19:086014|
|Kach, Jacob; Sandbo, Nathan; La, Jennifer et al. (2014) Antifibrotic effects of noscapine through activation of prostaglandin E2 receptors and protein kinase A. J Biol Chem 289:7505-13|
|Kach, Jacob; Sandbo, Nathan; Sethakorn, Nan et al. (2013) Regulation of myofibroblast differentiation and bleomycin-induced pulmonary fibrosis by adrenomedullin. Am J Physiol Lung Cell Mol Physiol 304:L757-64|
|Sandbo, Nathan; Ngam, Caitlyn; Torr, Elizabeth et al. (2013) Control of myofibroblast differentiation by microtubule dynamics through a regulated localization of mDia2. J Biol Chem 288:15466-73|
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