SELENIUM-INDUCED GLAUCOMA

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DESCRIPTION (provided by applicant): Glaucoma, the second leading cause of irreversible blindness in the United States, is a group of disorders characterized by a progressive loss of retinal ganglion cells with associated loss of vision that is in most cases coincident with elevated intraocular pressure (IOP). Today and in the foreseeable future, those with glaucoma are clinically managed with pharmaceutical agents that lower IOP. Elevated IOP in those with glaucoma results from defective regulatory processes in the outflow pathway. Consequently, a current area of focus for glaucoma research and a program priority area for the National Eye Institute (Glaucoma Panel Program Objective #3) is to understand the molecular and cellular mechanisms that underlie the regulation of fluid flow through the human outflow pathway. During a recent safety review in a current selenium-supplementation intervention trial (the Nutritional Prevention of Cancer Trial) an increased incidence of primary open-angle glaucoma amongst participants, particularly women, in the selenium treatment group was uncovered. In the present proposal, we examine the effects of selenium on the biology of human trabecular meshwork cells and outflow function both in the presence and absence of 17 beta-estradiol. Hypothesized effects of selenium on outflow function are consistent with demonstrated effects of selenium on other cell types that include alterations in extracellular matrix turnover, cell cycle arrest and induction of apoptosis. The present study will examine these endpoints in cell and organ culture models and thus is innovative for at least two reasons: First, determination of selenium effects on cell biology in human outflow pathway will provide insight into and/or support for critical regulatory mechanisms that control outflow facility. Second, selenium treatment of outflow tissues may provide a novel glaucoma model to study changes in the outflow pathways at the molecular and cellular level in a controlled manner. If successful, results obtained from these investigations will provide a basic understanding of selenium effects on aqueous outflow facility, uncover novel therapeutic targets for glaucoma treatment and generate a foundation for future investigations.