Racial disparities of open angle glaucoma: A study of mitochondria and oxidative stress in human trabecular meshwork

开角型青光眼的种族差异：人类小梁网线粒体和氧化应激的研究

• 批准号: 10735655
• 负责人: CARLA J SIEGFRIED
• 金额: $ 54.54万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735655
• 关键词: 8-hydroxy-2' -deoxyguanosine; Acceleration; Affect; African American; African ancestry; Age; Aggressive course; Antioxidants; Aqueous Humor; B-Lymphocytes; Bioenergetics; Biological; Black Populations; Black race; Blindness; Blood; Cell Culture Techniques; Cells; Classification; Complex; Cornea; DNA Markers; Data; Development; Disease; Disease Progression; Disparity; Drug Metabolic Detoxication; Elements; Exposure to; Eye; Eye Banks; Foundations; Free Radicals; Functional disorder; Gene Expression; Genes; Genetic; Genotype; Glaucoma; Glutathione; Goals; Goniotomies; Haplogroup; High Prevalence; Homeostasis; Human; In Situ Hybridization; Individual; Knowledge; Link; Measurement; Measures; Metabolism; Metformin; Mitochondria; Mitochondrial DNA; Monkeys; Niacinamide; Open-Angle Glaucoma; Operative Surgical Procedures; Organelles; Oxidation-Reduction; Oxidative Stress; Oxidative Stress Induction; Oxygen; Oxygen Consumption; Partial Pressure; Pathogenesis; Pathway interactions; Patient Self-Report; Patients; Persons; Physiologic Intraocular Pressure; Physiological; Population Study; Predisposition; Prevention; Primary Open Angle Glaucoma; Production; Protons; Public Health; Publishing; RNA; Race; Reactive Oxygen Species; Reporting; Research; Risk; Risk Factors; Severities; Specimen; Stratification; Stress; Superoxide Dismutase; System; Testing; Therapeutic; Thick; Tissues; Trabecular meshwork structure; Vision research; Visual impairment; Western Blotting; Work; anterior chamber; antioxidant enzyme; aqueous; black patient; catalase; cell injury; differential expression; disease disparity; early onset; human study; improved; innovation; insight; interest; mitochondrial metabolism; modifiable risk; neuroprotection; novel; novel therapeutics; nuclear factor-erythroid 2; oxidative DNA damage; oxidative damage; personalized therapeutic; precision medicine; pressure; prevent; protein expression; racial difference; racial disparity; superoxide dismutase 1; transcriptome sequencing; ubiquinol

Project Abstract: Understanding the pathogenesis of glaucoma, a leading cause of blindness worldwide, is an important goal of vision research. As indicated in numerous population-based studies, individuals of African descent develop glaucoma at an earlier age with increased severity and risk of blindness. 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 associated with basic genetic and physiologic differences in oxygen metabolism leading to disparities in glaucoma based on racial background. Our hypothesis is based on intraocular measurements of oxygen partial pressure (pO2) made in the human eye during surgery. We identified strong correlations between pO2 and important risk factors for glaucoma, including central corneal thickness and African-American/Black (B) heritage. In addition, measurements of a cell marker for DNA oxidative damage were elevated in the aqueous humor of B patients with severe glaucoma compared to W patients. Cultured TM cells from B healthy donors compared to W cells had altered energy (ATP) and reactive oxygen species production, implicating the energy processing organelles, the mitochondria. Our specific aims will test these hypotheses: (Aim 1) will evaluate differences in TM gene expression between B and W donor controls and in patients at various glaucoma stages in order to identify the genetic basis of disparities in tissue function (controlling eye pressure) and susceptibility to damage. Genes of interest will be further studied (RT-qPCR, in situ hybridization) and delineate protein expression (Western blot) in the tissue and potential biological pathways involved, focusing on mitochondrial function, oxidative stress and antioxidant protection. (Aim 2A) will study mitochondrial functions in primary human TM cell cultures from specimens of B and W healthy donor controls and glaucoma patients at various severity stages. We will determine the effects of racial differences and exposure to varying levels of pO2 on detailed analyses of mitochondrial quantities and function, reactive oxygen species levels and antioxidant protection. (Aim 2B) will also assess the cellular effects of potential antioxidative therapies. The proposed research is innovative because understanding these physiological mechanisms potentially contributing to disease disparity based on racial ancestry, confirmed by blood and tissue ancestral genotyping and mitochondrial DNA haplogroup stratification, will provide important information about the pathophysiology of open angle glaucoma by identifying factors responsible for the TM dysfunction and loss of aqueous outflow facility. The knowledge gained in these studies may lead to new therapies and strategies to prevent this blinding disease.

项目摘要： 了解青光眼的发病机理是全球失明的主要原因，是一个重要的目标 视力研究。如许多基于人群的研究所示，非洲血统的个体 在更早的年龄发展青光眼，严重程度增加和失明风险。许多研究有 鉴定出对小梁网（TM）细胞的氧化损伤，导致流出设施减少和 眼内压力增加。尽管将氧化损伤与青光眼联系起来的证据很强，但 青光眼中氧化损伤的原因尚不清楚。在拟议的研究中，我们将检验假设 对TM的氧化损伤与氧基本遗传和生理差异有关 代谢导致基于种族背景的青光眼差异。我们的假设是基于 手术过程中人眼中对氧氧局部压（PO2）的眼内测量。我们 鉴定出PO2与青光眼重要危险因素之间的强相关性，包括中央角膜 厚度和非裔美国人/黑色（B）遗产。另外，DNA细胞标记的测量值 与W相比 患者。与W细胞相比，B健康供体的培养的TM细胞的能量改变了（ATP）和 活性氧的产生，涉及能量加工细胞器，线粒体。我们的 具体目的将检验这些假设：（目标1）将评估B之间TM基因表达的差异 以及在各种青光眼阶段的供体对照和患者中 组织功能的差异（控制眼压）和损伤的易感性。感兴趣的基因将 进一步研究（RT-QPCR，原位杂交）和描述蛋白表达（Western blot） 组织和潜在的生物学途径，重点是线粒体功能，氧化应激和 抗氧化剂保护。 （AIM 2A）将研究来自原代人TM细胞培养物中的线粒体功能 B和W健康供体对照和青光眼患者的标本处于各种严重性阶段。我们将 确定种族差异和暴露于不同水平的PO2对详细分析的影响 线粒体量和功能，活性氧水平和抗氧化剂保护。 （AIM 2B） 还将评估潜在抗氧化疗法的细胞作用。拟议的研究是创新的 因为了解这些生理机制可能导致基于疾病差异的 关于种族血统，由血液和组织祖先基因分型和线粒体DNA单倍群证实 分层，将提供有关开头青光眼的病理生理学的重要信息 确定导致TM功能障碍和水性流出设施损失的因素。知识 在这些研究中获得的可能会导致新的疗法和策略，以防止这种盲目疾病。