Mechanisms of Shear-Regulated Vein Graft Remodeling

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): This proposed 5-year training program seeks to expand the applicant's knowledge in advanced molecular genetics with two primary goals: 1) advance his basic research into a hypothesis-driven, mechanistic understanding of vascular remodeling; and 2) provide him the skills needed to develop a translational research program for the application of gene therapy to the clinical environment. Key training components have been integrated to accomplish these goals and include didactic instruction in advanced genetics, fundamental coursework in the conduct of clinical investigation, and a research experience focusing on the techniques of in vivo gene delivery and modulation. The training has been thoughtfully constructed to help the applicant reach his long-term career goal of an independent basic research program that develops potential strategies to prevent vein graft narrowing and occlusion. The proposed research program incorporates several unique components at the University of Florida: 1) the Institute for Wound Research with expertise in the growth factor signaling of extracellular matrix reorganization; 2) the national Vector Laboratory with proficiency in viral gene delivery techniques; and 3) pioneering research in the application of ribozymes for in vivo gene inhibition. The proposed research focuses on the clinically relevant problem of vein bypass graft failure and examines the mechanisms underlying accelerated intimal hyperplasia development. Biomechanical forces have been identified as potent regulators of intimal thickening, yet an understanding of the underlying signaling mechanism remains limited. This proposal builds on our established rabbit model of flow-regulated vein graft remodeling and preliminary data suggesting connective tissue growth factor (CTGR) and gelatinases (MMP-2 and -9) to be key regulators of the remodeling process. We hypothesize that transforming growth factor (TGF-beta1), acting through CTGF, is a primary regulator of MMP activity within the remodeling vein graft wall. Specifically, we hypothesize that elevated wall shear stress within vein grafts induces an increase in TGF-beta1 production. Acting through an up-regulation of CTGF, this results in a decrease in MMP-2 and -9 activities within the vessel wall, inhibiting smooth muscle cell migration and proliferation and leading to a reduction in intimal hyperplasia. Using antisense oligonucleotide and ribozyme techniques to inhibit TGF-beta1 and CTGF In vivo, the mediators through which alterations in shear at the endothelium induce changes in the media and developing neointima will be characterized. Insight into these signaling pathways, in combination with development of these powerful gene inhibition techniques, offers the potential for direct application to the clinical setting.