Grants We Funded

Abstract
During wound healing under ischemic conditions, tissues have certain ingredients in their environmental milieu that vary both in content and amount from the surrounding normal tissue. These changes are the tissues' way of compensating for or trying to overcome the deleterious conditions that otherwise leads to poor or incomplete wound healing. For instance, hypoxiainducible factor 1 (HIP -1) is produced in large amounts by ischemic cells and is known to promote neovascularization via induction of vascular endothelial growth factor (VEGF) production. We would like to take advantage of these known differences in environmental make up, and specifically the presence of increased levels of HIP-l to increase the expression of genes that are known to promote more rapid skin wound closure, including VEGF and keratinocyte growth factor-2 (KGF-2). Our method is to link one of these genes to a sequence of DNA, known as a promoter region, that, when activated, turns up gene production of genes that are downstream from the promoter. By linking one of these genes to a promoter that is activated by HIP-l and introducing it to cells in an ischemic environment, we can increase cellular production of this gene by allowing HIP -1 to bind to the promoter region and activate cellular production of the gene. Furthermore, we will be able to control exactly where the upregulation occurs, since only a hypoxic environment will possess elevated HIP-l levels, thus affording targeted gene expression. We have generated a viral vector with the promoter region hypoxia-response element (HRE) linked to genes known to be active in wound healing. In addition, we have created a novel wound healing model in the rat that provides ischemic and non-ischemic wounds on the same animal, allowing for direct comparisons between the two wound healing conditions. We now are ready to introduce the viral vector into wounds to see if we can drive increased gene expression and wound healing in the presence of HIP -1.