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.
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