SELENIUM-INDUCED GLAUCOMA

描述（由申请人提供）：青光眼是美国不可逆性失明的第二大原因，是一组以视网膜神经节细胞的进行性丧失和相关视力丧失为特征的疾病，在大多数情况下伴有眼压升高。在今天和可预见的将来，青光眼患者在临床上使用降低IOP的药物治疗。青光眼患者IOP升高的原因是流出通道的调节过程有缺陷。因此，目前青光眼研究的一个重点领域和国家眼科研究所（青光眼小组项目目标#3）的一个项目优先领域是了解通过人体流出通道调节液体流动的分子和细胞机制。

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.