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）：了解青光眼的发病机理是失明的第二主要原因，是视力研究的重要目标。许多研究已经确定了对小梁网（TM）细胞的氧化损伤，从而导致流出设施降低并增加了眼内压。尽管将氧化损伤与青光眼联系起来的证据很强，但尚不清楚青光眼氧化损伤的原因。在拟议的研究中，我们将检验以下假设：TM对TM的氧化损害是由于过度暴露于分子氧和/或其代谢物而引起的。我们的假设基于对手术期间使用薄，柔性，光纤探针在人眼中制成的氧局部压（PO2）的测量。我们确定了前腔中的大，稳定的氧梯度，并在靠近TM的前室角度鉴定了PO2的紧密调节。我们还注意到PO2与青光眼重要的风险因素之间的密切相关性，包括中央角膜厚度，非裔美国人遗产以及玻璃体切除术手术史。我们认为，我们的研究是第一个将生理变量PO2（AC）中的PO2与青光眼发育的风险联系起来的。我们的第一个具体目标将测试玻璃体切除术后青光眼的风险增加是否是由于AC中的PO2增加，从而损害了TM。我们将与威斯康星大学麦迪逊分校的同事合作，在较老的恒河猕猴中进行一项纵向研究，该研究将依次接受玻璃体切除术手术和白内障提取。我们将在每个阶段绘制PO2水平，并测量幽默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，并量化对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的氧化损伤相关联。我们的第二个目的是确定非洲裔美国人的PO2是否与水性幽默的生化变化相关。我们将在水性幽默中扩大对代谢物的试点研究，这表明线粒体代谢的种族差异。我们还将分析幽默的总抗氧化剂潜力和已知抗氧化剂（如抗坏血酸）的浓度。研究将确定PO2与前室中氧化剂抗氧化剂平衡之间是否存在相关性。我们假设较高的PO2将与抗氧化剂的耗竭有关。我们的第三个具体目的是确定角膜氧代谢的非侵入性测量是否预测了眼内PO2。我们假设较低的角膜氧的消耗将与AC中的PO2增加相关。如果正确，该测试可能会提供一种重要手段，以确定患有青光眼风险的人。它还将提供一种方法来确定眼内氧的差异是否遗传并识别所涉及的基因。我们的新方法将通过确定导致水性流出设施损失的因素来提供有关开角青光眼的病理生理学的重要信息。这些研究获得的知识可能会导致新的疗法和预防这种疾病的策略。 公共卫生相关性：众多研究为氧化应激，破坏自由基分子和人体的抗氧化剂防御机制之间的失衡而提供了支持，通过损害伊斯兰排水管中的小径网状细胞以及潜在损害光学细胞的细胞来在青光眼中发挥作用。我们假设这种损害的根源是由于小梁网状细胞过度暴露于氧气和/或其代谢物引起的。我们将评估氧气水平升高的影响，我们已经与几个先前确定的青光眼风险因素有关，对动物模型中小梁网的功能和细胞变化的影响。我们还将研究眼睛的流体，以实现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：青光眼是全世界失明的第二大主要原因，也是美国频繁的视觉障碍原因，是一个重要的公共卫生问题。通过扩展我们对这种情况原因的理解，该研究建议还将扩展潜在的治疗和预防途径。