SELENIUM-INDUCED GLAUCOMA

描述(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进行性丧失为特征的疾病，并伴有相关的视力丧失，在大多数情况下与眼压升高相一致。现在和可预见的未来，青光眼患者的临床治疗是通过降低眼压的药物来进行的。青光眼患者的高眼压是由于流出通道的调节过程有缺陷所致。因此，目前青光眼研究的一个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)是了解通过人类流出途径调节液体流动的分子和细胞机制。 在最近的一项目前的补硒干预试验(癌症营养预防试验)的安全性审查中，发现在硒治疗组的参与者中，尤其是妇女中，原发性开角型青光眼的发病率增加。在目前的建议中，我们研究了在存在和不存在17β-雌二醇的情况下，硒对人眼小梁细胞生物学和流出功能的影响。假设的硒对流出功能的影响与已证实的对其他类型细胞的影响是一致的，包括改变细胞外基质周转、细胞周期停滞和诱导细胞凋亡。本研究将在细胞和器官培养模型中检验这些终点，因此具有创新性，至少有两个原因：第一，确定硒在人类流出途径中对细胞生物学的影响将为控制流出设施的关键调控机制提供洞察和/或支持。其次，硒对流出组织的治疗可能提供一种新的青光眼模型，在分子和细胞水平上以受控的方式研究流出途径的变化。 如果成功，这些研究的结果将使人们对硒对房水流出设施的影响有一个基本的了解，发现治疗青光眼的新的治疗靶点，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.