Ocular Oxygen Metabolism and the Etiology of Open Angle Glaucoma

眼氧代谢与开角型青光眼的病因学

• 批准号: 8086516
• 负责人: CARLA J SIEGFRIED
• 金额: $ 63.86万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8086516
• 关键词: Accounting; African American; Animal Model; Antioxidants; Aqueous Humor; Biochemical; Blindness; Carnitine; Cataract Extraction; Cell Respiration; Cell physiology; Cells; Clinic; Contact Lenses; Cornea; Data; Defense Mechanisms; Development; Disease; Equilibrium; Etiology; Exposure to; Extracellular Matrix; Eye; Free Radicals; Functional disorder; Future; Genes; Genetic; Glaucoma; Goals; Human; Hydrogen Peroxide; Inherited; Intraocular Lens Implantation; Knowledge; Lead; Link; Liquid substance; Longitudinal Studies; Macaca mulatta; Maps; Measurement; Measures; Mediator of activation protein; Metabolism; Methods; Mitochondria; Molecular; Open-Angle Glaucoma; Operative Surgical Procedures; Optic Nerve; Oxidants; Oxidative Stress; Oxygen; Oxygen Consumption; Partial Pressure; Pathogenesis; Pathway interactions; Patients; Physiologic Intraocular Pressure; Physiological; Pilot Projects; Play; Prevention therapy; Public Health; Race; Recording of previous events; Regulation; Research Proposals; Retinal Ganglion Cells; Risk; Risk Factors; Role; Source; Staging; Testing; Thick; Trabecular meshwork structure; Universities; Vision research; Visual impairment; Vitrectomy; Wisconsin; anterior chamber; aqueous; ascorbate; base; cell injury; design; flexibility; gene discovery; glaucoma surgery; killings; metabolomics; novel strategies; oxidative damage; population based; prevent; racial difference; theories; therapy design

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.

描述（由申请人提供）：了解青光眼（导致失明的第二大原因）的发病机制是视力研究的一个重要目标。许多研究已经发现小梁网 (TM) 细胞受到氧化损伤，导致流出设施减少和眼内压升高。尽管有强有力的证据表明氧化损伤与青光眼有关，但青光眼氧化损伤的原因尚不清楚。在拟议的研究中，我们将检验这样的假设：TM 的氧化损伤是由于过度暴露于分子氧和/或其代谢物而引起的。我们的假设基于氧分压 (pO2) 的测量，该测量是在手术期间使用薄而灵活的光纤探头在人眼中进行的。我们发现前房内存在大而稳定的氧梯度，并且靠近 TM 的前房角内 pO2 受到严格调节。我们还注意到 pO2 与青光眼重要危险因素之间存在很强的相关性，包括中央角膜厚度、非裔美国人血统和玻璃体切除手术史。我们相信，我们的研究首次将前房 (AC) 中的 pO2 生理变量与青光眼发展的风险联系起来。我们的第一个具体目标是测试玻璃体切除术后青光眼风险的增加是否是由于 AC 中的 pO2 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，这些猕猴将依次接受玻璃体切除手术和白内障摘除术。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。我们的第二个目标是确定非裔美国人的 pO2 增加是否与房水的生化变化相关。我们将扩大对房水代谢物的初步研究，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（如抗坏血酸）的浓度；确定 pO2 与前房氧化-抗氧化平衡之间是否存在相关性的研究。我们假设较高的 pO2 与抗氧化剂的消耗有关。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耗氧量与 AC 中 pO2 的增加相关。如果正确的话，该测试可能会提供一种重要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的差异是否是遗传的，并鉴定所涉及的基因。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。这些研究中获得的知识可能会带来预防这种疾病的新疗法和策略。 公共健康相关性：大量研究支持这一理论，即氧化应激（破坏性自由基分子与人体抗氧化防御机制之间的不平衡）通过损害眼睛引流管中的小梁网细胞以及潜在地在青光眼中发挥作用。损害视神经细胞。我们假设这种损伤的根源是小梁网细胞过度暴露于氧气和/或其代谢物造成的。我们将评估氧气水平升高对动物模型中小梁网功能和细胞变化的影响，我们已将其与先前确定的几种青光眼危险因素相关联。我们还将研究眼睛液体中与氧化应激相关的生化变化，并测量角膜对氧气的使用，并避免使用隐形眼镜进行侵入性测量。相关性：青光眼是全球第二大失明原因，也是美国视力障碍的常见原因，是一个重要的公共卫生问题。通过扩展我们对这种疾病原因的理解，这项研究计划还将扩大潜在的治疗和预防途径。