THE UPA PATHWAY IN CORNEAL STROMA WOUND HEALING

描述（来自申请人摘要的逐字）：当角膜受伤时， 静止的基质角膜细胞发生了戏剧性的转化，首先转化为 运动的分泌性成纤维细胞，然后进入收缩准备，肌动蛋白丰富， 肌成纤维细胞对TGF-β的反应。肌成纤维细胞促进伤口闭合 但在成功愈合的伤口中几乎没有残留我们正在探索 尿激酶型纤溶酶原激活物（uPA）在这些表型中的作用 转换。uPA是一种丝氨酸蛋白酶，其促进细胞外基质 降解、细胞迁移、生长因子释放和组织侵袭 癌细胞和白细胞。我将检验角膜基质 细胞使用uPA调节角膜愈合，类似于其在侵入性角膜炎中的活性。 细胞这种模式是通过与其受体uPAR结合而激活的uPA， 从纤溶酶原产生局部纤溶酶，纤溶酶原又释放 生物活性FGF。FGF增加uPA分泌，产生更多纤溶酶 纤溶酶原当纤溶酶水平显著升高时， 活动释放活性TGF-β，抑制uPA分泌，并刺激 uPA抑制剂派的分泌，从而关闭生长因子信号传导。 uPAR除了结合uPA外，还与整合素和细胞外基质结合。 基质蛋白uPAR/整合素/基质缔合可能是 协同迁移和细胞外蛋白酶活性。

DESCRIPTION (Verbatim from applicant's abstract): When the cornea is wounded, there is a dramatic conversion of quiescent stromal keratocytes, first into motile, secretory fibroblasts, and then into contraction-ready, actin-rich myofibroblasts in response to TGF-beta. Myofibroblasts promote wound closure but few, if any, remain in a successfully-healed wound. We are exploring the role of urokinase-type plasminogen activator (uPA) in these phenotype conversions. uPA is a serine protease that promotes extracellular matrix degradation, cell migration, growth factor release, and tissue invasion by cancer cells and leukocytes. I will test the hypothesis that corneal stroma cells use uPA to regulate corneal healing analogous to its activity in invasive cells. The paradigm is that uPA, activated by binding to its receptor; uPAR, generates localized plasmin from plasminogen, which in turn releases biologically-active FGF. FGF increases uPA secretion, generating more plasmin from plasminogen. When plasmin levels are significantly elevated, plasmin activity releases active TGF-beta, which inhibits uPA secretion, and stimulates secretion of a uPA inhibitor, PAI, thus turning off growth factor signaling. uPAR, in addition to binding uPA, associates with integrins and extracellular matrix proteins uPAR/integrin/matrix association may be required for coordinated migration and extracellular protease activity.