Metalloproteinase Expression in Corneal Wounds

描述(申请人提供)：背景：角膜新生血管是世界范围内致盲的主要原因。本研究的目的是明确膜型基质金属蛋白酶1(MT1-MMPs)在角膜新生血管形成中的作用及其蛋白分解功能。我们的实验室已经发现MT1-MMPs存在于角膜中，并切割抗血管生成的片段，在角膜伤口愈合过程中可能调节角膜新生血管的形成。 假设：在角膜损伤过程中，基质成纤维细胞产生膜型基质金属蛋白酶(MT1-MMPs)，通过三种机制介导角膜新生血管(NV)：细胞外基质(ECM)分解、角膜抗血管生成因子降解和血管内皮生长因子(VEGF)转录上调。 具体目标： MT1-MMPs在角膜新生血管中的分布和酶活性 B.评价角膜血管生成的第一条途径：角膜细胞膜相关MT1-MMPECM的分解。 评估角膜血管生成的第二途径：角膜细胞来源的MT1-基质金属蛋白酶降解角膜抗血管生成因子。 评估角膜血管生成的第三条途径：MT1-基质金属蛋白酶诱导基质角质细胞中血管内皮生长因子转录上调。 意义：了解维持角膜无血管的机制可能使我们能够预防由角膜新生血管引起的失明。对角膜中MT1-MMPs的研究可能为其在角膜新生血管形成和伤口愈合中的临床意义提供有价值的信息。

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.