This proposal describes a five-year development program for an academic career in vascular surgery. The principal investigator is board certified in general and vascular surgery and is pursuing further training as a scientist. Through an intense basic science research experience he will acquire 1) advanced skills in molecular and cell biology; and 2) an expertise in extracellular matrix (ECM) remodeling, matrix metalloproteinases (MMP) and ischemic limb angiogenesis. Limb ischemia can result in gangrene and amputation. Current therapies are often invasive and of limited success. The scientific aim of this proposal is to test the hypothesis that type-IV collagenase-mediated remodeling of type-IV collagen exposes cryptic epitopes that regulate angiogenesis and revascularizationin ischemic limbs. This proposal is based on two sets of observations. First, preliminary data suggest there is a significant increase in type-IV collagenase (i.e., MMP-2, -9) activity in the muscle of ischemic limbs. Second, proteolysis of collagen-IV exposes cryptic epitopes that are inaccessible in mature, native collagen-IV. These epitopes may play a role in the biochemical regulation of angiogenesis in ischemic limbs via cell-matrix interactions in the collagen-IV rich basement membrane of blood vessels. Specifically, essential information for the biochemical regulation of angiogenesis in ischemic limbs may be hidden within the three-dimensional structure of ECM molecules. There is currently little direct evidence available concerning the mechanisms by which molecular remodeling in the ECM is regulated and contributes to angiogenesis. This project will try to identify and characterize this novel regulatory process, which may be significant for the revascularization and salvage of ischemic limbs.
| Hobeika, Mark J; Thompson, Robert W; Muhs, Bart E et al. (2007) Matrix metalloproteinases in peripheral vascular disease. J Vasc Surg 45:849-57 |
| Gagne, Paul J; Tihonov, Nikita; Li, Xialou et al. (2005) Temporal exposure of cryptic collagen epitopes within ischemic muscle during hindlimb reperfusion. Am J Pathol 167:1349-59 |
