CORNEAL EPITHELIAL DIFFERENTIATION AND REGENERATION

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The long range goal of this project is to understand the mechanisms of corneal development, maintenance and regeneration. The results will be applicable to the better management of corneal healing and prevention of blindness. The research strategy is to evaluate the functional significance of changes in the expression of specific proteins which are regulated during these processes. We are focusing on a Rho (Ras homology)-associated in serine/threonine kinase (ROCK-I) whose expression is significantly increased in the corneal epithelial cells after they migrate from the limbal to corneal surface. Rho belongs to the Ras family of small GTPases, which control a variety of cellular processes involving cell proliferation, actin filament reorganization and phospholipid metabolism. ROCK-I is one of the downstream components of Rho signaling pathways. Our immediate goals are to understand the mechanisms of ROCK-I involvement in the signaling cascade in the corneal epithelium. To achieve these goals, our specific aims are to test the following hypotheses: 1) ROCK-I is involved in corneal epithelial migration, differentiation and proliferation and that these functions of ROCK-I require its intracellular translocation. This will be tested in vitro in cultured rabbit corneal epithelial cells. 2) Phosphorylation by a cAMP-dependent protein kinase (PKA) is involved in controlling the enzyme activity and nuclear translocation of ROCK-1. 3) diacylglycerol (DAG), a second messenger formed by receptor triggered hydrolysis of phosphotidyl inositol, 4, 5 biphosphate (PIP2), promotes the intracellular translocation of ROCK-I. These studies will lead to the identification of RhoA and ROCK-I signaling elements which may be specific targets for new drugs, useful for modulating corneal epithelial repair.