This proposal will provide new training and a significant shift in career direction for the PI from fields of quantitative biophysics and nanotechnology to biomedical research in cardiovascular diseases. The proposal will draw on the expertise and mentoring of pioneering investigators engaged in heart and lung research at the Davis Heart and Lung Research Institute at the Ohio State University in Columbus, OH. The overall experimental plan aims to investigate the role of recently discovered collagen-binding receptors, the discoidin domain receptors (DDRs) in myocardial matrix remodeling. Two fundamentally novel facts about DDR-collagen interactions have emerged from out preliminary data: (1) DDRs inhibit fibrillogenesis of collagen type 1, and (2) DDRs recognize the fibrillar state of collagen. These findings have led us to investigate the role of DDRs in myocardial matrix remodeling via two specific aims: (1) how does the expression of only the DDR extracellular domain affect collagen deposition, and (2) how do DDRs regulate the fibrillar state of collagen and development of fibrosis. Studies will be carried out at the molecular and cellular level and on human heart failure tissue obtained from cases with and without myocardial infaction. These investigations will be critical in elucidating novel mechanisms of myocardial matrix remodeling by DDRs. This proposal will combine the biophysical and microscopic expertise of the PI with the molecular and matrix biology competency of the team of mentors and thus provide two complementary experimental approaches for biomedical research. Another primary goal of this application is enable the PI to acquire expertise in the molecular and matrix biology techniques and the background necessary in cardiovascular physiology to develop as an independent researcher in biomedicine.
| Yeung, David; Chmielewski, David; Mihai, Cosmin et al. (2013) Oligomerization of DDR1 ECD affects receptor-ligand binding. J Struct Biol 183:495-500 |
| Flynn, Lisa A; Blissett, Angela R; Calomeni, Edward P et al. (2010) Inhibition of collagen fibrillogenesis by cells expressing soluble extracellular domains of DDR1 and DDR2. J Mol Biol 395:533-43 |
| Blissett, Angela R; Garbellini, Derek; Calomeni, Edward P et al. (2009) Regulation of collagen fibrillogenesis by cell-surface expression of kinase dead DDR2. J Mol Biol 385:902-11 |
| Mihai, Cosmin; Chotani, Maqsood; Elton, Terry S et al. (2009) Mapping of DDR1 distribution and oligomerization on the cell surface by FRET microscopy. J Mol Biol 385:432-45 |
