The goal of this application is to expand upon the scientific skills of this applicant ultimately producing an independent investigator capable of a lifetime of clinically relevant scientific contributions. The project described below focuses on the role of alpha3beta1 integrin in epithelial-mesenchymal transition (EMT) and pulmonary fibrosis. This applicant has already spent several years studying pulmonary fibrosis, both as a resident and clinical fellow. During these years, this applicant has mastered several basic research techniques. While the studies described below will allow further refinement and the gain of several new techniques, we believe that the pursuit of becoming an independent investigator involves considerable conceptual training in critical thought, innovation, scientific writing, mentoring and the ability to establish collaborations. Thus, the career development plan will include focused course work, participation in a number of scientific meetings and collaboration with other investigators. During the past two years we have been exploring the mechanism by which alpha3betal regulates TGFbeta1, a critical cytokine in the pathogenesis of fibrosis and a key regulator of EMT. We have also developed tools for further investigation, including two compound transgenic mouse systems. The first is a doxycycline-inducible, alveolar epithelial cell (AEC)-specific loss of alpha3beta1. The second system involves doxycycline-inducible, AEC-specific and permanent expression of a reporter gene, allowing us to track the fate of these cells as they potentially differentiate into mesenchymal cells. Both of these mice are already available and the systems have been verified by multiple techniques. Furthermore, we have mastered techniques at isolating and culturing primary AECs and have already used these tools to demonstrate AEC transition into mesenchymal cells and to support a critical role for alpha3beta1 in regulating this process. The scientific goals during this award period will be to explore the function of alpha3beta1 in AECs, determine the factors which regulate EMT, and to determine the importance of alpah3beta1 and EMT in animal models of pulmonary fibrosis. Despite years of research, pulmonary fibrosis remains a devastating problem without good therapy. With greater understanding into this relatively unexplored pathway, a new paradigm for the pathogenesis of fibrosis may emerge with the potential for novel and more effective therapies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
7K08HL085290-05
Application #
8096900
Study Section
Special Emphasis Panel (ZHL1-CSR-O (F1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2007-04-01
Project End
2012-06-30
Budget Start
2010-09-01
Budget End
2011-06-30
Support Year
5
Fiscal Year
2010
Total Cost
$121,204
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Yang, Jibing; Velikoff, Miranda; Canalis, Ernesto et al. (2014) Activated alveolar epithelial cells initiate fibrosis through autocrine and paracrine secretion of connective tissue growth factor. Am J Physiol Lung Cell Mol Physiol 306:L786-96
Yang, Jibing; Wheeler, Sarah E; Velikoff, Miranda et al. (2013) Activated alveolar epithelial cells initiate fibrosis through secretion of mesenchymal proteins. Am J Pathol 183:1559-1570
Ulsamer, Arnau; Wei, Ying; Kim, Kevin K et al. (2012) Axin pathway activity regulates in vivo pY654-?-catenin accumulation and pulmonary fibrosis. J Biol Chem 287:5164-72
Courey, Anthony J; Horowitz, Jeffrey C; Kim, Kevin K et al. (2011) The vitronectin-binding function of PAI-1 exacerbates lung fibrosis in mice. Blood 118:2313-21
Marmai, Cecilia; Sutherland, Rachel E; Kim, Kevin K et al. (2011) Alveolar epithelial cells express mesenchymal proteins in patients with idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 301:L71-8
Kim, Young; Kugler, Matthias C; Wei, Ying et al. (2009) Integrin alpha3beta1-dependent beta-catenin phosphorylation links epithelial Smad signaling to cell contacts. J Cell Biol 184:309-22
Kim, Kevin K; Wei, Ying; Szekeres, Charles et al. (2009) Epithelial cell alpha3beta1 integrin links beta-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosis. J Clin Invest 119:213-24
Kim, Kevin K; Chapman, Harold A (2007) Endothelin-1 as initiator of epithelial-mesenchymal transition: potential new role for endothelin-1 during pulmonary fibrosis. Am J Respir Cell Mol Biol 37:1-2