The long term objective of this project is to determine the role of cortisol and its metabolites in the pathogenesis of primary open angle glaucoma (POAG) and to develop therapeutic modalities which are of value in the treatment of this disease. it has been hypothesized that the cells of the outflow pathway region in patients with POAG accumulate 5beta-dihydro-cortisol (5beta-DHF) which is responsible for their sensitivity to the intraocular pressure (IOP) raising effect of glucocorticoids and for their ocular hypertension. This hypothesis has led to the discovery of 3alpha, 5beta-tetrahydrocortisol (3alpha, 5beta-THF), a metabolite of 5beta-DHF which is ocularly hypotensive in rabbits made ocular hypertensive with glucocorticoids and in patients with POAG. This naturally occurring antiglucocorticoid represents a new class of compounds for the treatment of POAG. Studies of the enzymes responsible for the formation of 5beta-DHF (cortisol-4-5beta-reductase) and for the conversion of 5beta-DHF to 3alpha, 5beta-THF (3alpha-hydroxy- steroid dehydrogenase (3alpha-HSD)) as well as a study of the biological effect of these metabolites are proposed. The prevalence and molecular basis for the enzyme defects in POAG will be analyzed in non-cultured human outflow tissue using monoclonal antibodies and cRNAs to these enzymes. The mechanisms by which 5beta-DHF potentiates glucocorticoid activity will be studied using homogenates of rabbit iris-ciliary body and cultures of normal human trabecular meshwork (HTM) cells. Additional glucocorticoid antagonists will be identified using the dexamethasone-induced secretion of fibronectin in cultured HTM cells as an assay system. Those antagonists which show activity in tissue culture will be tested for their effects on IOP and aqueous humor dynamics in rabbits made ocular hypertensive with glucocorticoids. Inhibitors of cortisol-4-5beta-reductase (to reduce the accumulation of 5beta-DHF) and inducers of 3alpha-HSD (to increase the conversion of 5beta-DHF to 3alpha-5beta-THF, an ocularly hypotensive metabolite) will be identified using cultured normal HTM cells. These enzyme inhibitors and inducers represent possible new modalities of POAG therapy.
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