Mitochondrial Respiratory Chain Dysfunction in Primary Open Angle Glaucoma

原发性开角型青光眼的线粒体呼吸链功能障碍

• 批准号: 10086649
• 负责人: Qi N Cui
• 金额: $ 4.9万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10086649
• 关键词: ATP Synthesis Pathway; Affect; African; African American; Age; Autosomal Dominant Optic Atrophy; Binding Sites; Blindness; Blood Platelets; Cell Death; Cell Line; Complex; Country; Cytochrome-c Oxidase Deficiency; DNA; Data; Databases; Development Plans; Disease; Drainage procedure; Electron Transport; Environment; Etiology; Evaluation; Exhibits; Eye; Fostering; Functional disorder; Funding; Generations; Genes; Genetic Databases; Genetic study; Glaucoma; Haplogroup; Harvest; Human; Hybrids; Impairment; Inherited; Institutes; Investigation; K-Series Research Career Programs; Knowledge; Leber' s Hereditary Optic Neuropathy; Literature; Mentorship; Methods; Microspheres; Missense Mutation; Mitochondria; Mitochondrial DNA; Mitochondrial Diseases; Modeling; Mus; Mutant Strains Mice; Mutation; Nuclear; OPA1 gene; Ocular Hypertension; Ophthalmology; Optic Disk; Optic Nerve; Oxidases; Oxidative Stress; Oxygen; Pathogenesis; Pathogenicity; Patients; Pediatric Hospitals; Pennsylvania; Personal Growth; Phenotype; Philadelphia; Physiologic Intraocular Pressure; Play; Population; Predisposition; Primary Open Angle Glaucoma; Process; Protons; Reactive Oxygen Species; Research; Research Personnel; Research Training; Respiration; Respiratory Chain; Retina; Retinal Ganglion Cells; Role; Scientist; Scotoma; Secondary to; Severities; Single Nucleotide Polymorphism; Site; Techniques; Testing; Time; Trabecular meshwork structure; Training; Universities; Variant; Vision; Visual Fields; anterior chamber; base; career development; case control; complex IV; cytochrome c oxidase; disorder risk; experience; geographic population; high risk; human subject; individualized medicine; male; mitochondrial DNA mutation; mitochondrial dysfunction; mitochondrial genome; mouse model; mutant; optic nerve disorder; overexpression; respiratory; sex; stressor; success

Project Summary/Abstract: A growing body of evidence suggests that secondary mitochondrial dysfunction underlies numerous complex diseases including glaucoma. Primary open angle glaucoma (POAG) is the most common form of glaucoma. It represents a group of disorders with population-associated variations in course and severity, which likely signify differences in pathogenesis, some of which may be associated with mitochondrial dysfunction. Mitochondrial haplogroups correspond to maternally-determined geographic populations, and may be protective or confer a higher risk for certain diseases. Utilizing the Primary Open- Angle African-American Glaucoma Genetics database, the PI found worse glaucomatous cupping and more severe visual field loss in the L1c2 haplogroup compared to the closely associated L1b haplogroup despite comparable age, sex, and intraocular pressure (IOP). L1c2 is defined by two missense mutations affecting the mitochondrial gene cytochrome c oxidase I (COI), which encodes a key component of the mitochondrial electron transport/respiratory chain (RC) Complex IV. The RC is the site of ATP synthesis and a primary site for reactive oxygen species generation, disturbances of which have been implicated in glaucoma. In mice with a COI mutation and reduces Complex IV activity, the PI found decreased number of RGCs in male mutants compared to controls, suggesting decreased RC function predisposes to optic neuropathies such as ones resulting from glaucoma. The PI hypothesizes that inherited variations of RC subunits cause impaired mitochondrial respiration, which confers increased susceptibility to RGC loss and to additional stressors like elevated IOP, manifesting as glaucomatous optic neuropathy. Specific aims will: 1) Determine the ocular phenotype and mitochondrial function in a murine model of COI mutation at baseline and in the setting of induced ocular hypertension; and 2) assess the ocular phenotype and mitochondrial function in POAG patients with COI mutations. By optimizing methods of RC functional assessment, this research has the potential to transform the evaluation of cellular respiratory disturbances in glaucoma. Associating disease risks with haplogroup designations constitutes an important step towards individualized glaucoma treatment. The PI will conduct the research under the mentorship of experienced investigators from the University of Pennsylvania (UPenn) and the Children's Hospital of Philadelphia. UPenn is an ideal setting for training clinician-scientists, and the Scheie Eye Institute, in particular, is among the best in the country for research training. The ophthalmology department is committed to fostering success, and has provided the PI with protected time, dedicated space, institutional funds, and a nurturing environment. The PI has mastered multiple techniques included in this proposal and has developed a comprehensive career development plan to facilitate personal growth. By the end of the K award period, the PI will have gained the knowledge needed to mature into an independent investigator who will advance the understanding and treatment of glaucoma.

项目摘要/摘要：越来越多的证据表明继发性线粒体功能障碍 是包括青光眼在内的许多复杂疾病的基础。原发性开角型青光眼(POAG)是最常见的 常见的青光眼。它代表了一组与人群相关的疾病的病程变化 和严重性，这可能意味着发病机制的不同，其中一些可能与 线粒体功能障碍。线粒体单倍群对应于母体决定的地理位置 而且可能对某些疾病具有保护性或更高的风险。利用初级开放- 角度非裔美国人青光眼遗传学数据库中，PI发现青光眼拔火罐更严重 与密切相关的L1B单倍组相比，L1c2单倍组的视野严重丧失，尽管 相同的年龄、性别和眼压(IOP)。L1c2由两个影响L1c2的错义突变定义 线粒体基因细胞色素C氧化酶I(COI)，它编码线粒体的一个关键成分 电子传递/呼吸链(RC)复合体IV.RC是ATP合成的部位和主要部位 对于活性氧的产生，其紊乱已被认为与青光眼有关。在小鼠中 COI突变并降低复合体IV活性，PI发现雄性突变体中RGC数量减少 与对照组相比，表明减少了 RC 功能 易患视神经疾病，如 由青光眼引起的。PI假设RC亚基的遗传变异导致功能受损 线粒体呼吸，这增加了对RGC丢失和其他应激源的易感性，如 眼压升高，表现为青光眼视神经病变。具体目标将：1)决定眼睛 COI突变小鼠模型在基线和背景下的表型和线粒体功能 2)评估POAG患者的眼部表型和线粒体功能。 有COI突变。通过优化RC功能评估的方法，本研究有可能 改变对青光眼细胞呼吸障碍的评估。将疾病风险与 单倍组指定构成了走向个体化青光眼治疗的重要一步。 国际和平研究所将在加州大学经验丰富的调查人员的指导下进行这项研究 宾夕法尼亚州(UPenn)和费城儿童医院。宾夕法尼亚大学是一个理想的培训场所 临床科学家，特别是Scheie眼科研究所，是全国最好的研究机构之一 训练。眼科致力于培养成功，并为PI提供了 受保护的时间、专用的空间、机构资金和培育环境。PI已经掌握了多个 并制定了一个全面的职业发展计划，以促进 个人成长。到K奖金期结束时，PI将获得成熟所需的知识 成为一名独立的调查者，他将推动对青光眼的理解和治疗。