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 disorder. Most patients with POAG show a marked sensitivity to the intraocular pressure raising effects of topical and systemic glucocorticoids. It has been our working hypothesis that this is related to an abnormality in cortisol metabolism in ocular tissue. Indeed, an alteration in cortisol metabolism has recently been demonstrated in cells cultured from human trabeculectomy specimens from POAG patients (TMPOAG cells). This alteration in metabolism led to an accumulation of dihydrocortisol, an intermediate not found in nonglaucomatous trabecular meshwork cells (TMPOAG cells). Further, dihydrocortisol was shown to potentiate both cortisol and dexamethasone-induced nuclear translocation of the cytoplasmic glucocorticoid receptor in the rabbit iris-ciliary body. These observations suggest a mechanism for the sensitivity of POAG patients to exogenous glucocorticoids and for the ocular hypertension seen in these same patients. Techniques have been developed for culturing of cells from trabecular meshwork specimens (surgical and autopsy) that will allow us to test our hypothesis of an etiologic relationship between abnormal cortisol metabolism and POAG. Additional TMPOAG and TMnonPOAG cell lines will be developed to determine the incidence of the aberrant cortisol metabolism in POAG. Studies with TM cells from patients with secondary glaucoma will serve as controls for the effects of prior glaucoma therapy and chronic ocular hypertension. The enzymatic basis for this altered cortisol metabolism in TMPOAG cell lines will be investigated. The effects of enzyme inhibitors and inducers will be studied in order to determine whether the abnormal accumulation of dihydrocortisol can be prevented. In addition, glucocorticoid antagonists may be found to block the dihydrocortisol potentiation of glucorticoid-induced nuclear translocation of its receptor and its subsequent biological effects. Those antagonists that are found to be of value in in vitro studies of the human ouflow region (angle) will be studied for their ability to block the pressure raising effects of glucocorticoids and their metabolites in young rabbits. These studies may lead to information that can become the basis for new therapies (enzyme modifiers and glucocorticoid antagonists) for the treatment of POAG.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
3R01EY001313-16S1
Application #
3255874
Study Section
Clinical Sciences Study Section (CLN)
Project Start
1979-08-01
Project End
1992-03-31
Budget Start
1990-09-30
Budget End
1992-03-31
Support Year
16
Fiscal Year
1991
Total Cost
Indirect Cost
Name
New York Medical College
Department
Type
Schools of Medicine
DUNS #
City
Valhalla
State
NY
Country
United States
Zip Code
10595
Weinstein, B I; Iyer, R B; Binstock, J M et al. (1996) Decreased 3 alpha-hydroxysteroid dehydrogenase activity in peripheral blood lymphocytes from patients with primary open angle glaucoma. Exp Eye Res 62:39-45
Southren, A L; Wandel, T; Gordon, G G et al. (1994) Treatment of glaucoma with 3 alpha, 5 beta-tetrahydrocortisol: a new therapeutic modality. J Ocul Pharmacol 10:385-91
Binstock, J M; Iyer, R B; Hamby, C V et al. (1992) Human hepatic 3 alpha-hydroxysteroid dehydrogenase: possible identity with human hepatic chlordecone reductase. Biochem Biophys Res Commun 187:760-6
Weinstein, B I; Kandalaft, N; Ritch, R et al. (1991) 5 alpha-dihydrocortisol in human aqueous humor and metabolism of cortisol by human lenses in vitro. Invest Ophthalmol Vis Sci 32:2130-5
Iyer, R B; Binstock, J M; Schwartz, I S et al. (1990) Human hepatic cortisol reductase activities: enzymatic properties and substrate specificities of cytosolic cortisol delta 4-5 beta-reductase and dihydrocortisol-3 alpha-oxidoreductase(s). Steroids 55:495-500
Hernandez, M R; Weinstein, B I; Schwartz, J et al. (1987) Human trabecular meshwork cells in culture: morphology and extracellular matrix components. Invest Ophthalmol Vis Sci 28:1655-60
Southren, A L; l'Hommedieu, D; Gordon, G G et al. (1987) Intraocular hypotensive effect of a topically applied cortisol metabolite: 3 alpha, 5 beta-tetrahydrocortisol. Invest Ophthalmol Vis Sci 28:901-3
Gerritsen, M E; Weinstein, B I; Gordon, G G et al. (1986) Prostaglandin synthesis and release from cultured human trabecular-meshwork cells and scleral fibroblasts. Exp Eye Res 43:1089-102
Southren, A L; Hernandez, M R; l'Hommedieu, D et al. (1986) Potentiation of collagen synthesis in explants of the rabbit eye by 5 beta-dihydrocortisol. Invest Ophthalmol Vis Sci 27:1757-60
Hernandez, M R; Weinstein, B I; Dunn, M W et al. (1985) The effect of dexamethasone on the synthesis of collagen in normal human trabecular meshwork explants. Invest Ophthalmol Vis Sci 26:1784-8

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