Glaucoma is a blinding eye disease. Understanding of the regulation of intraocular pressure and ways of decreasing aqueous humor inflow could lead to improved clinical glaucoma therapies. The ability to obtain isolated ocular cell types involved in secretion of aqueous humor permits evaluation of neurogastro-intestinal (NG) hormones as possible modulators of this aspect of aqueous humor dynamics. The basis for this R-29 first grant proposal in ophthalmology will be to more fully approach the role of certain classes of drugs which appear to be potential physiological and/or pharmacological regulators of aqueous flow in glaucoma research. Vasoactive intestinal peptide and other neurotransmitters (and local hormones) known to affect NG epithelia appear also to regulate human nonpigmented ciliary epithelial (NPE) cells in our initial studies. These findings could be quite important to developing an improved understanding of the control mechanisms over aqueous humor secretion. In this proposal cultured human NPE will be compared to the morphologically differentiated pigmented (CPE) ciliary epithelium we have also recently established in vitro. Pharmacological and biochemical characterization of the specific receptors for VIP and other NG agonists will be conducted as well as an examination of agonist/antagonist effects of these regulators. We will also begin to examine the biochemical responses to agonist activities, including phosphorylation of specific NPE proteins and calcium changes. Based on dose-response data and drug interactions defined in vitro, we also plan in vivo studies of potential aqueous in flow effects in collaboration with Dr. Kaufman.
