Candidate Goals and Career Development Plan: The candidate is a vascular surgeon with the long-term goal of becoming an independent investigator in an academic medical center. The candidate has learned skills in the basic research of intimal hyperplasia and of integrin-extracellular matrix (ECM) interactions. This award will provide support needed to develop the foundation of knowledge and skills required for successful long-term investigation. This foundation will be built over the proposed five years of the award by (1) understanding integrin-ECM interactions in vascular disease; (2) determining the interaction of matrix metalloproteinases (MMPs) to the integrin-ECM complex leading to cell movement; and (3) gathering data for the development of an independent project in the pathophysiology of intimal hyperplasia. Environment: The environment is rich in the availability of integrin and extracellular matrix expertise. The candidate's sponsor is well recognized as an independent investigator of ECM and MMPs and has had numerous successes in developing funded independent investigators. The candidate has a well-equipped laboratory and a full-time research technician whose salary is supported by the department. Research Proposal: The primary aim is to investigate the role of integrins in vascular smooth muscle cell (SMC migration and in formation of intimal hyperplasia and restenosis. Preliminary data indicate that beta3 integrin is critical to early SMC migration from aortic explants and early intimal lesion development after arterial injury. Moreover, collagen-binding integrins, alpha1beta1 and alpha2beta1, appear to be critical to late SMC migration from explants. Therefore, we plan to identify the collagen-binding integrin(s) important in SMC-collagen ex vivo and in late SMC migration in vivo. Next, we plan to understand the role of collagenases in the interplay of SMC migration on native collagen. Finally, we will block the critical pathways of SMC migration in vivo to eliminate intimal lesion formation.
| Kokubo, Taku; Ishikawa, Noriyuki; Uchida, Hisashi et al. (2009) CKD accelerates development of neointimal hyperplasia in arteriovenous fistulas. J Am Soc Nephrol 20:1236-45 |
| Kokubo, Taku; Uchida, Hisashi; Choi, Eric T (2007) Integrin alpha(v)beta(3) as a target in the prevention of neointimal hyperplasia. J Vasc Surg 45 Suppl A:A33-8 |
| Choi, Eric T; Collins, Emily T; Marine, Leopoldo A et al. (2005) Matrix metalloproteinase-9 modulation by resident arterial cells is responsible for injury-induced accelerated atherosclerotic plaque development in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 25:1020-5 |
| Choi, Eric T; Khan, M Faisal; Leidenfrost, Jeremy E et al. (2004) Beta3-integrin mediates smooth muscle cell accumulation in neointima after carotid ligation in mice. Circulation 109:1564-9 |
| Leidenfrost, Jeremy E; Khan, M Faisal; Boc, Kenneth P et al. (2003) A model of primary atherosclerosis and post-angioplasty restenosis in mice. Am J Pathol 163:773-8 |
