PROTEASES AND CORNEAL ULCERATION

角膜是一种独特的组织，因为它的无血管性质和透明度的要求。 因此，分子的局部合成比在其他组织中更重要。 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生成抑制剂血管生成抑制素的前体。 纤溶酶降解纤维蛋白和其他细胞外基质分子，并激活基质金属蛋白酶和生长因子。 总体假设角膜通过控制局部合成的保护性分子和组织重塑介质的水平来响应损伤（创伤和感染）。 与大多数其他组织相比，角膜局部调节纤溶酶原以及其他分子的水平，这些分子通常由肝脏合成并通过血管系统分布到组织。具体目标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中纤溶酶原合成以及纤溶酶原从血管系统扩散的影响。将角膜细胞体外合成纤溶酶原的能力与血管化组织的细胞进行比较。将检测角膜合成通常由肝脏合成的其他分子（纤维蛋白原和凝血酶原）的能力。 将使用兔将纤溶酶原和纤维蛋白原从血管系统体内流入角膜与正常伤口和感染条件下角膜合成这些分子进行比较。具体目标二：确定角膜中血管抑素样分子的生成机制，与活性酶纤溶酶的形成对照。 角膜衍生的血管抑素样分子的结构和生物活性将被确定。 将检测其他非恶性细胞产生血管抑制素样活性的能力。 血管抑素的生产和控制这一过程中所涉及的机制将进行探讨。 将测试控制纤溶酶与血管抑制素产生的几种拟议机制。 将鉴定参与血管抑制素样肽产生的蛋白酶。

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.