Ocular Oxygen Metabolism and the Etiology of Open Angle Glaucoma

描述（由申请人提供）：了解青光眼的发病机制是视力研究的重要目标，青光眼是致盲的第二大原因。许多研究已经发现氧化损伤小梁网（TM）细胞，导致流出设施减少和眼压升高。虽然氧化损伤与青光眼相关的证据很充分，但青光眼氧化损伤的原因尚不清楚。在拟议的研究中，我们将验证TM氧化损伤是由过度暴露于分子氧和/或其代谢物引起的假设。我们的假设是基于在手术中使用薄而灵活的光纤探针在人眼中测量的氧分压（pO2）。我们发现前房的氧梯度大而稳定，前房角的pO2调节紧密，接近TM。我们还注意到pO2与青光眼的重要危险因素有很强的相关性，包括角膜中央厚度、非裔美国人血统和玻璃体切割手术史。我们相信我们的研究是第一个将生理变量前房pO2 （AC）与青光眼发展风险联系起来的研究。我们的第一个具体目的是测试玻璃体切除术后青光眼风险的增加是否由于AC中pO2的增加而导致TM损伤。我们将与威斯康星大学麦迪逊分校的同事合作，对老年恒河猴进行纵向研究，这些恒河猴将依次接受玻璃体切除术和白内障摘除手术。我们将绘制pO2水平图，并测量每个阶段的房水抗氧化剂和流出设施。在研究结束时，我们将确定TM细胞损失的程度，并量化TM细胞及其细胞外基质的结构和氧化损伤。通过这种方式，我们可以将pO2与TM的氧化损伤联系起来。我们的第二个目的是确定非裔美国人pO2的增加是否与房水中的生化变化有关。我们将扩大对房水中代谢物的初步研究，该研究表明线粒体代谢的种族差异。我们还将分析房水的总抗氧化潜力和已知抗氧化剂的浓度，如抗坏血酸；这些研究将确定pO2与前房氧化-抗氧化平衡之间是否存在相关性。我们假设较高的pO2将与抗氧化剂的消耗有关。我们的第三个具体目的是确定角膜氧代谢的无创测量是否能预测眼内pO2。我们假设较低的角膜耗氧量与AC中pO2的增加有关。如果正确，该测试可能为确定青光眼风险提供重要手段。它还将提供一种方法来确定眼内氧的差异是否遗传，并确定相关基因。我们的新方法将通过确定导致水流出设施丧失的因素，为开角型青光眼的病理生理学提供重要信息。在这些研究中获得的知识可能会导致新的治疗方法和预防这种疾病的策略。

DESCRIPTION (provided by applicant): Understanding the pathogenesis of glaucoma, the second leading cause of blindness, is an important goal of vision research. Many studies have identified oxidative damage to the trabecular meshwork (TM) cells, leading to decreased outflow facility and increased intraocular pressure. Although the evidence linking oxidative damage to glaucoma is strong, the causes of oxidative damage in glaucoma are not known. In the proposed studies, we will test the hypothesis that oxidative damage to the TM is caused by excessive exposure to molecular oxygen and/or its metabolites. Our hypothesis is based on measurements of oxygen partial pressure (pO2), made in the human eye during surgery using a thin, flexible, fiberoptic probe. We identified large, stable oxygen gradients in the anterior chamber and tight regulation of pO2 in the anterior chamber angle, close to the TM. We also noted strong correlations between pO2 and important risk factors for glaucoma, including central corneal thickness, African-American heritage, and history of vitrectomy surgery. We believe that our studies are the first to link a physiologic variable, pO2 in the anterior chamber (AC), to these risks of glaucoma development. Our first specific aim will test whether the increased risk of glaucoma after vitrectomy is due to increased pO2 in the AC, causing damage to the TM. We will collaborate with colleagues at the University of Wisconsin-Madison for a longitudinal study in older Rhesus macaques that will sequentially undergo vitrectomy surgery and cataract extraction. We will map pO2 levels and measure aqueous humor antioxidants and outflow facility at each stage. At the conclusion of the study, we will determine the extent of TM cell loss and quantify the structural and oxidative damage to TM cells and their extracellular matrix. In this manner, we may correlate pO2 with oxidative damage to the TM. Our second aim is to determine whether the increased pO2 in African- Americans correlates with biochemical changes in the aqueous humor. We will expand our pilot study of metabolites in the aqueous humor, which suggested racial differences in mitochondrial metabolism. We will also analyze aqueous humor for its total antioxidant potential and concentration of known antioxidants, like ascorbate; studies that will determine whether there is a correlation between pO2 and the oxidant-antioxidant balance in the anterior chamber. We hypothesize that higher pO2 will be associated with depletion of anti- oxidants. Our third specific aim is to determine whether a non-invasive measure of corneal oxygen metabolism predicts intraocular pO2. We hypothesize that lower corneal oxygen consumption will correlate with increased pO2 in the AC. If correct, this test may provide an important means to determine those at risk of developing glaucoma. It will also offer a method to determine whether differences in intraocular oxygen are inherited and to identify the genes involved. Our novel approach will provide important information about the pathophysiology of open angle glaucoma by identifying factors responsible for the loss of aqueous outflow facility. The knowledge gained in these studies may lead to new therapies for and strategies to prevent this disease. PUBLIC HEALTH RELEVANCE: Numerous studies provide support for the theory that oxidative stress, the imbalance between damaging free radical molecules and the body's antioxidant defense mechanisms, plays a role in glaucoma by damaging the trabecular meshwork cells in the drain of the eye and also by potentially damaging the cells of the optic nerve. We hypothesize that the source of this damage is caused by excessive exposure of the trabecular meshwork cells to oxygen and/or its metabolites. We will evaluate the effects of elevated levels of oxygen, which we have correlated to several previously identified glaucoma risk factors, on the function and cellular changes of the trabecular meshwork in an animal model. We will also study the fluids of the eye for biochemical changes associated with oxidative stress and measure the cornea's use of oxygen and avoid invasive measurements with a contact lens. Relevance: Glaucoma, the second leading cause of blindness worldwide and frequent cause of visual impairment in the U.S., is an important public health issue. By extending our understanding of the causes of this condition, this research proposal will also expand potential pathways of therapy and prevention.