Metalloproteinase Expression in Corneal Wounds

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DESCRIPTION (provided by applicant): Background: Corneal neovascularization is a major cause of blindness worldwide. The objective of our research is to identify the role of membrane type 1 matrix metalloproteinase (MT1-MMP) and its proteolytic functions in corneal neovascularization. Our laboratory has found that MT1-MMP is present in the cornea and cleaves anti-angiogenic fragments which may regulate corneal neovascularization during corneal wound healing. Hypothesis: During corneal wounding, stromal fibroblasts generate membrane-type matrix metalloproteinase (MT1-MMP), which mediates corneal neovascularization (NV) by three mechanisms: breakdown of the extracellular matrix (ECM), degradation of corneal anti-angiogenic factors, and transcriptional up-regulation of vascular endothelial growth factor (VEGF). Specific aims: A. MT1-MMP Distribution and Enzymatic Activity in Corneal Neovascularization. B. Evaluation of 1st Pathway of Corneal Angiogenesis: ECM Breakdown by Keratotocyte Membrane-Associated MT1-MMP. C. Evaluation of the 2nd Pathway of Corneal Angiogenesis: Keratocyte-derived MT1-MMP Degradation of Corneal Anti-angiogenic Factors. D. Evaluation of the 3rd Pathway of Corneal Angiogenesis: MT1-MMP-Induced Transcriptional Upregulation of VEGF in Stromal Keratocytes. Significance: Understanding the mechanisms that maintain corneal avascularity may allow us to prevent blindness caused by corneal neovascularization. The study of MT1-MMP in the cornea may provide valuable information about their possible clinical significance in corneal neovascularization and wound healing.