Ocular Oxygen Metabolism and the Etiology of Open Angle Glaucoma

描述(申请人提供)：了解青光眼的发病机制，青光眼是导致失明的第二大原因，是视力研究的重要目标。许多研究已经证实了小梁细胞的氧化损伤，导致流出能力降低和眼压升高。尽管将氧化损伤与青光眼联系在一起的证据很强，但青光眼中氧化损伤的原因尚不清楚。在拟议的研究中，我们将检验这一假设，即TM的氧化损伤是由于过度暴露于分子氧和/或其代谢产物造成的。我们的假设是基于对氧分压(PO2)的测量，这是在手术过程中使用细小、灵活的光纤探头在人眼中进行的。我们在前房内发现了大而稳定的氧气梯度，并在接近TM的前房角内严格调节了PO2。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，包括中央角膜厚度、非裔美国人血统和玻璃体手术史。我们相信，我们的研究首次将生理变量--前房血氧饱和度与青光眼发生的风险联系起来。我们的第一个具体目标是测试玻璃体手术后青光眼风险的增加是否是由于AC中PO2的增加，从而对TM造成损害。我们将与威斯康星大学麦迪逊分校的同事合作，对老年恒河猴进行一项纵向研究，随后将进行玻璃体切除手术和白内障摘除。我们将绘制PO2水平图，并在每个阶段测量房水、抗氧化剂和流出设施。在研究结束时，我们将确定TM细胞丢失的程度，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。我们的第二个目标是确定非裔美国人增加的PO2是否与房水中的生化变化有关。我们将扩大我们对房水中代谢物的初步研究，这表明线粒体代谢存在种族差异。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；研究将确定PO2与前房中氧化-抗氧化平衡是否存在相关性。我们假设，较高的PO2将与抗氧化剂的耗尽有关。我们的第三个具体目标是确定角膜氧代谢的非侵入性测量是否可以预测眼内PO2。我们假设，较低的角膜氧耗量将与AC中的PO2增加相关。如果正确，这项测试可能会提供一种重要的手段来确定那些有患青光眼风险的人。它还将提供一种方法来确定眼内氧气的差异是否是遗传的，并识别涉及的基因。我们的新方法将通过识别导致房水流出设施丧失的因素，提供有关开角型青光眼病理生理学的重要信息。从这些研究中获得的知识可能会导致预防这种疾病的新疗法和策略。

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.