Metalloproteinase Expression in Corneal Wounds

背景：角膜新生血管形成是全球失明的主要原因。我们的研究目的是确定膜1型基质金属蛋白酶（MT1-MMP）及其蛋白水解功能在角膜新生血管中的作用。我们的实验室发现，MT1-MMP存在于角膜中，并分裂出抗血管生成碎片，这些碎片可能在角膜伤口愈合过程中调节角膜新生血管。

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.