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: 10219262
• 负责人: Qi N Cui
• 金额: $ 22.74万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219262
• 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。它代表了一组在病程中具有人群相关变化的疾病 和严重程度，这可能意味着发病机制的差异，其中一些可能与 线粒体功能障碍线粒体单倍型群对应于母系决定的地理 这可能对某些人群具有保护作用，或增加某些疾病的风险。利用主要的开放- 角非裔美国人青光眼遗传学数据库，PI发现更糟糕的青光眼拔罐和更多 与密切相关的L1 b单倍型组相比，L1 c2单倍型组的严重视野丧失， 年龄、性别和眼内压（IOP）相当。L1 c2由两个错义突变定义， 线粒体基因细胞色素c氧化酶I（COI），其编码线粒体的关键组分 电子传递/呼吸链（RC）复合物IV。RC是ATP合成的位点，也是ATP合成的主要位点。 用于活性氧物质的产生，活性氧物质的紊乱与青光眼有关。小鼠 由于COI突变并降低复合物IV活性，PI发现雄性突变体中RGC数量减少 与对照组相比， RC 功能 易患视神经病变， 由青光眼引起的。PI假设RC亚基的遗传变异导致受损 线粒体呼吸，这赋予增加的易感性RGC损失和额外的压力，如 眼压升高，表现为青光眼性视神经病变。具体目标将：1）确定眼睛 表型和线粒体功能在COI突变的小鼠模型中在基线和在 2）评估POAG患者的眼表型和线粒体功能 COI突变。通过优化RC功能评估方法，本研究具有潜在的 改变青光眼中细胞呼吸紊乱的评估。将疾病风险与 单倍型组指定构成了个体化青光眼治疗的重要一步。 主要研究者将在香港大学经验丰富的研究人员的指导下进行研究。 宾夕法尼亚大学和费城儿童医院。宾夕法尼亚大学是一个理想的培训环境 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 训练眼科部门致力于促进成功，并为PI提供了 保护时间、专用空间、机构资金和培育环境。私家侦探掌握了多种 技术，并制定了全面的职业发展计划，以促进 个人成长在K奖励期结束时，PI将获得成熟所需的知识 成为一个独立的研究者，将促进对青光眼的理解和治疗。

项目成果

Orbital magnetic resonance imaging of giant cell arteritis with ocular manifestations: a systematic review and individual participant data meta-analysis.

具有眼部表现的巨细胞动脉炎的轨道磁共振成像：系统评价和个体参与者数据荟萃分析。

• DOI: 10.1007/s00330-023-09770-2
• 发表时间: 2023
• 期刊: European radiology
• 影响因子: 5.9
• 作者: Guggenberger,KonstanzeV;Pavlou,Athanasios;Cao,Quy;Bhatt,IshaanJ;Cui,QiN;Bley,ThorstenA;Curtin,HughD;Savatovsky,Julien;Song,JaeW
• 通讯作者: Song,JaeW

Elevated IOP following a bladder filling protocol: A case report.

• DOI: 10.1016/j.ajoc.2022.101786
• 发表时间: 2023-03
• 期刊: American journal of ophthalmology case reports
• 作者: Qin, Vivian L;Nguyen, Brian J;Tripp, Patrick;Lehman, Amanda;Addis, Victoria M;Cui, Qi N
• 通讯作者: Cui, Qi N