The overall goal of this research is to understand the mechanism of ocular inflammation in terms of the chemical mediators derived from arachidonic acid metabolism and their receptors on target cells. This knowledge will provide a framework for the development of improved therapeutic approaches to the inflamed eye and any disorder involving the products of arachidonic acid metabolism. Our recent studies have clearly demonstrated specific receptors for prostaglandins in ocular tissue. We now hypothesize that the diverse actions of prostaglandins in the eye are related to the properties and distribution of highly specific receptor subtypes. Before we can relate receptor properties to prostaglandin action in the eye, it is crucial that we fully elucidate the receptor characteristics. We will use sophisticated radioligand binding studies to characterize the prostaglandin receptor subtypes in terms of specificity, density and affinity. Receptor binding properties will then be related to cellular function by measuring second messengers of the signal transduction pathways (i.e. cyclic AMP, IP3 and calcium) coupled to prostanoid receptors in fresh ocular tissue and cultured cells. We further hypothesize that the action of prostaglandins in the eye can be modified by modulation of receptors and their respective signal transduction pathways. We will therefore elucidate the mechanisms of up and down regulation of the receptors and signal transduction pathways under conditions where prostaglandin synthesis and production have been modified by NSAID or corticosteroids and also under conditions where cell receptors have been chronically exposed to receptor agonists. This in depth knowledge of prostaglandin receptors is a prerequisite for gaining a better understanding of prostaglandin actions in the eye.
