CONTROL OF CORNEAL HYDRATION AND TRANSPARENCY

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The goal of this proposal is to understand the processes that control the movements of the fluid into and out of the corneal transparency is frequently due to edema, an exessive accumulation of fluid in the stroma which causes it to swell and become opaque. The sungle layer of cells on the posterioe surface, the endothelium, controls the hydration of the stroma by allowing a limited amount of fluid to be drawn in from the aqueous humor (the leak), and expelling an equivalent amount by energy- dependent active transport process (the pump). The proposed Aims will examine three mechanisms by which the pump and leak function of the endothelial cells may be regulated. Each of the studies, which encompass biochemical, pharmacological and physiological approaches, will be done with whole corneas, allowing direct correlation of the observations with the hydration state of stroma. Aim 1 examines the transduction pathways (second messengers) and the effector mechanisms (sodium pump, ion channels, permeability) that mediate improves (i.e., decreased) hydration in response to adenosine. Aim 2 studies the question of of signalling (feedback) from stromal hydration or volume of the endothelial cells themselves in regualtion of pump or leak funcations. Aim 3 examines the dependence of endothelial cell structure (tight junctions, cytoskeleton) and enzyme activity (Na+-K+ATPase, cyclase, kinase) on the endogenous levels of ATP. Understanding these systems that modulate the fluid transport characteristics of the endothelium create opportunity for therapeutic intervention that would stimulate pump activity or decrease the leak, thereby controlling the edema seen in such conditions as diabetes or hepetic keratitis.