This proposal describes a 5-year training program for my development of an academic career in vascular surgery. Through an integrated program between the Department of Vascular Surgery and the Department of Pharmacology and Toxicology, a command of intracellular signaling mechanisms, as applied to vascular disease, will be secured. Dr. Richard J. Powell, M.D., will mentor the principal investigator's scientific development. Dr. Powell is an NIH-funded researcher in vascular biology with extensive experience with a bi-layer co-culture model used to better define the effects of endothelial cells (ECs) on vascular smooth muscle cells (VSMCs) function and behavior. Dr. Powell has trained numerous residents and fellows who have gone on to successful academic careers. To enhance the training, this program will enlist the expertise of Dr. Kathleen A. Martin, Assistant Professor of Surgery and of Pharmacology and Toxicology. She is an expert in intracellular signaling mechanisms, specifically the mTOR pathway. In addition, an advisory committee of highly regarded scientists will provide scientific and career advice. My research will focus on the intracellular signaling mechanisms involved in phenotypic modulation, migration and proliferation of VSMCs. Rapamycin inhibits VSMC proliferation, protein synthesis and migration in vitro. We have recently demonstrated that rapamycin stimulates VSMC differentiation. VSMC differentiation was determined by contractile morphology and upregulation of contractile proteins. Rapamycin inhibits mTOR, a signaling protein known to regulate translation initiation pathways. The downstream effectors of the mTOR pathway, which modulate these pleomorphic effects, have not been determined.
The specific aims i nclude: 1) to determine whether rapamycin sensitive mTOR downstream effectors S6K1 or S6K2 oppose VSMC differentiation; 2) to determine whether rapamycin sensitive mTOR downstream effector 4E-BP1/elF-4E oppose VSMC differentiation; and 3) to determine if rapamycin effects are similar in VSMC from different vascular beds. The long-term objective is to determine the signaling pathways which mediate the VSMC intimal hyperplastic response, with the aim of identifying novel, cell-type specific targets for therapeutic intervention.
| Wagner, Robert J; Martin, Kathleen A; Powell, Richard J et al. (2010) Lovastatin induces VSMC differentiation through inhibition of Rheb and mTOR. Am J Physiol Cell Physiol 299:C119-27 |
| Rzucidlo, Eva M; Martin, Kathleen A; Powell, Richard J (2007) Regulation of vascular smooth muscle cell differentiation. J Vasc Surg 45 Suppl A:A25-32 |
