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（全球失明的主要原因）的发病机制是一个重要目标 的视觉研究。正如大量基于人口的研究表明，非洲人后裔 青光眼的发病年龄较早，严重程度和失明风险都会增加。许多研究已经 确定了小梁网（TM）细胞的氧化损伤，导致流出设施减少和 眼压升高。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，我们将检验假设 TM 的氧化损伤与氧气的基本遗传和生理差异有关 新陈代谢导致基于种族背景的青光眼差异。我们的假设基于 手术期间在人眼中进行的氧分压 (pO2) 的眼内测量。我们 确定了 pO2 与青光眼重要危险因素（包括中央角膜）之间的密切相关性 厚度和非裔美国人/黑人 (B) 血统。此外，DNA 细胞标记物的测量 与 W 相比，B 重度青光眼患者房水中氧化损伤升高 患者。与 W 细胞相比，来自 B 健康供体的培养 TM 细胞的能量 (ATP) 和 活性氧的产生，涉及能量处理细胞器线粒体。我们的 具体目标将检验这些假设：（目标 1）将评估 B 之间 TM 基因表达的差异 和 W 供体对照以及不同青光眼阶段的患者，以确定青光眼的遗传基础 组织功能（控制眼压）和损伤易感性的差异。感兴趣的基因将 进一步研究（RT-qPCR、原位杂交）并描绘蛋白质表达（蛋白质印迹） 涉及的组织和潜在的生物学途径，重点关注线粒体功能、氧化应激和 抗氧化保护。 （目标 2A）将研究原代人类 TM 细胞培养物中的线粒体功能 B 和 W 健康供体对照和不同严重程度阶段的青光眼患者的标本。我们将 确定种族差异和暴露于不同氧分压水平对详细分析的影响 线粒体数量和功能、活性氧水平和抗氧化保护。 （目标 2B） 还将评估潜在抗氧化疗法的细胞效应。所提出的研究具有创新性 因为了解这些生理机制可能有助于基于疾病差异 通过血液和组织祖先基因分型以及线粒体 DNA 单倍群证实的种族血统 分层，将提供有关开角型青光眼病理生理学的重要信息 确定导致 TM 功能障碍和房水流出设施丧失的因素。知识点 这些研究的成果可能会带来新的疗法和策略来预防这种致盲疾病。