SELENIUM-INDUCED GLAUCOMA

描述（由申请人提供）：青光眼是美国不可逆失明的第二大主要原因，是一组以视网膜神经节细胞的进行性丧失为特征的疾病，伴有视力丧失，在大多数情况下与眼内压（IOP）升高一致。今天和在可预见的未来，青光眼患者在临床上使用降低IOP的药物进行治疗。青光眼患者的IOP升高是由于外流途径中的调节过程缺陷所致。因此，青光眼研究的当前重点领域和国家眼科研究所的计划优先领域（青光眼小组计划目标#3）是了解调节通过人类流出途径的流体流动的分子和细胞机制。 在最近的一项安全性审查中，在目前的硒补充干预试验（营养预防癌症试验）中，发现硒治疗组的参与者，特别是女性，原发性开角型青光眼的发病率增加。在目前的建议中，我们研究了硒对人类小梁网细胞的生物学和外流功能的影响，在存在和不存在17 β-雌二醇。硒对外流功能的假设影响与硒对其他细胞类型的影响一致，包括细胞外基质周转，细胞周期停滞和诱导凋亡的改变。本研究将在细胞和器官培养模型中检查这些终点，因此至少有两个原因是创新的：首先，确定硒对人类流出途径中细胞生物学的影响将为控制流出设施的关键调节机制提供洞察和/或支持。第二，硒治疗外流组织可能提供一种新的青光眼模型，以研究在分子和细胞水平上的外流途径的变化，在一个控制的方式。 如果成功的话，从这些研究中获得的结果将提供一个基本的了解硒对水流出设施的影响，发现新的治疗青光眼的治疗目标，并为未来的研究奠定基础。

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.