PROTEASES AND CORNEAL ULCERATION

角膜是一个独特的组织，因为它的无血管性质和它的透明度要求。因此，局部分子合成比其他组织更重要。我们的研究表明，在角膜中发现并由角膜合成的丝氨酸蛋白酶是纤溶酶原，纤溶酶的前体。以前，唯一已知的合成这种分子的肝外细胞是小胶质细胞。纤溶酶原可以作为纤溶酶和血管抑制素（一种血管生成抑制剂）的前体。纤溶蛋白降解纤维蛋白和其他细胞外基质分子，激活基质金属蛋白酶和生长因子。角膜对损伤（损伤和感染）的反应是通过控制局部合成的保护分子和组织重塑介质的水平来实现的。与大多数其他组织不同，角膜局部调节纤溶酶原以及通常由肝脏合成并通过血管系统分布到组织的其他分子的水平。特异性目的1：确定角膜合成纤溶酶原的能力是否异常，并确定损伤和感染对角膜内纤溶酶原合成和血管系统内纤溶酶原扩散的影响。角膜细胞体外合成纤溶酶原的能力将与血管化组织的细胞进行比较。将测试角膜合成通常由肝脏合成的其他分子，如纤维蛋白原和凝血酶原的能力。体内纤溶酶原和纤维蛋白原从血管系统流入角膜的情况将与正常伤口和感染条件下角膜合成这些分子的情况进行比较。特异性目的2：确定角膜中血管抑制素样分子的生成机制，与活性酶，纤溶酶的形成形成对比。角膜源性血管抑制素样分子的结构和生物活性将被确定。其他非恶性细胞的细胞的能力将被测试产生血管抑制素样活性的能力。血管抑制素的产生和控制的机制将被探讨。将测试几种拟议的控制纤溶酶和血管抑制素产生的机制。在血管抑制素样肽的生产过程中所涉及的蛋白酶将被确定。

The cornea is a unique tissue because of its avascular nature and its requirement for transparency. As a result, local synthesis of molecules is more important than in other tissues. Our studies have shown that the serine proteinase found in and synthesized by the cornea is plasminogen the precursor of the enzyme plasmin. Previously, the only known extrahepatic cell that synthesizes this molecule is the microglia cell. Plasminogen can serve as a precursor of plasmin and the angiostatin, an angiogenesis inhibitor. Plasmin degrades fibrin, and other extracellular matrix molecules and activates matrix metalloproteinases and growth factors. Overall hypothesis The cornea responds to insults (wounding and infection) by controlling the levels of protective molecules and mediators of tissue remodeling by local synthesis. In contrast to most other tissues, the cornea locally regulates the levels of plasminogen as well as other molecules normally synthesized by the liver and distributed through the vascular system to tissues. Specific Aim 1: To determine whether the cornea is unusual in its ability to synthesize plasminogen and to determine the effect of injury and infection on the synthesis of plasminogen in the cornea and on diffusion of plasminogen from the vascular system. The ability of the corneal cells to synthesize plasminogen in vitro will be compared to that of cells of vascularized tissues. The ability of the cornea to synthesize other molecules normally synthesized by the liver, fibrinogen and prothrombin, will be tested. The influx of plasminogen and fibrinogen from the vascular system into the cornea in vivo will be compared to the synthesis of these molecules by the cornea under normal wound and infection conditions using rabbits. Specific Aim 2: To determine in the cornea the mechanism for generation of angiostatin-like molecules in contrast to the formation of the active enzyme, plasmin. The structure and biological activity of cornea derived angiostatin-like molecules will be determined. The ability of cells of other non-malignant cells will be tested for ability to produce angiostatin-like activity. The mechanisms involved in angiostatin production and control of this process will be explored. Several proposed mechanisms for controlling plasmin vs angiostatin production will be tested. The proteinase(s) involved in the production of the angiostatin-like peptides will be identified.