CORNEAL ENDOTHELIAL REPAIR--ROLE OF LIPID MEDIATORS

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The overall objective of this project is to elucidate the mechanisms governing wound repair in the corneal endothelium. The central hypothesis to be explored in the proposed studies, is that arachidonate derived lipid mediators synthesized in response to injury or to extracellular signals modulate the progression of the corneal endothelial cell through its cycle of mitosis and differentiation. The aims of the proposed study are to: 1) identify the modulatory lipid mediators of the corneal endothelium, 2) characterize the production of such mediators by mitotic and differentiating endothelial cells, 3) determine if receptor-dependent signal transduction is regulated in mitotic and differentiated endothelial cells, 4) explore post-receptor signal signal effector pathways that govern lipid mediator regulation of mitosis and differentiation in corneal endothelial cells and 5) compare lipid mediated regulation of mitosis and differentiation in rabbit human corneal endothelial cells. These questions will be investigated using mitotic, differentiated and wound closure models of rabbit corneal endothelial cells grown in tissue culture, and using organ culture models of human corneal endothelium. Lipid mediators regulating mitosis and differentiation will be identified using cyctochemical detection of cell cycle and differentiation markers. Biosynthesis of mediators and regulation of receptor mediated events will be determined using biochemical tracers, immunoassay of biosynthetic enzymes and biochemical assay of second messengers. The involvement of intracellular effector pathways will be investigated using pharmacological probes to alter signal transduction pathways. Lipid mediators found to alter mitosis and differentiation of rabbit corneal endothelium will also be tested using organ culture models of and dystrophic human corneal endothelium. The results obtained from these studies will suggest therapeutic strategies for enhancing corneal endothelial wound repair subsequent to accidental or surgical trauma.