THE UPA PATHWAY IN CORNEAL STROMA WOUND HEALING

描述(逐字摘自申请者摘要)：当角膜受伤时， 静止的基质角质细胞有戏剧性的转化，首先是 活动的、分泌的成纤维细胞，然后变成收缩准备好的富含肌动蛋白的细胞 肌成纤维细胞对转化生长因子-β的反应。肌成纤维细胞促进伤口闭合 但几乎没有人，如果有的话，留在一个成功愈合的伤口。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，可促进细胞外基质 降解、细胞迁移、生长因子释放和组织侵袭 癌细胞和白细胞。我将测试角膜基质的假说 细胞使用uPA调节角膜愈合，类似于其在侵袭性中的活性 细胞。其模式是uPA，通过与其受体结合而激活；uPAR， 纤溶酶原产生局部纤溶酶，继而释放 具有生物活性的成纤维细胞生长因子。成纤维细胞生长因子增加uPA的分泌，产生更多的纤溶酶 是纤溶酶原引起的。当纤溶酶水平显著升高时，纤溶酶 活性释放活性的转化生长因子-β，抑制uPA的分泌，并刺激 分泌uPA抑制剂PAI，从而关闭生长因子信号转导。 UPAR除了与uPA结合外，还与整合素和细胞外结合 可能需要基质蛋白uPAR/整合素/基质结合 协调迁移和胞外蛋白酶活性。

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.