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

基本信息

批准号：
10018873
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
项目类别：
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/10018873
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&apos 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

项目摘要

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次级线粒体功能障碍构成了包括青光眼在内的许多复杂疾病。主要的开角青光眼（POAG）是最大的青光眼的常见形式。它代表了一组与人群相关的疾病和严重程度，这可能表示发病机理的差异，其中一些可能与线粒体功能障碍。线粒体单倍体对应于母体确定的地理人群，可能具有保护性或赋予某些疾病的较高风险。利用主要开放角度非裔美国人青光眼遗传学数据库，PI发现较差的青光眼拔罐和更多与密切相关的L1B单倍群相比，L1C2单倍群的严重视野损失尽管可比的年龄，性别和眼内压（IOP）。 L1C2由两个影响的错义突变定义线粒体基因细胞色素C氧化酶I（COI），它编码线粒体的关键成分电子传输/呼吸链（RC）复合物IV。 RC是ATP合成的位置和主要部位对于活性氧的产生，其干扰与青光眼有关。在老鼠中 COI突变并降低复合物IV活性，PI发现雄性突变体的RGC数量减少与对照组相比，建议减少 RC 功能易感性神经病（例如患者）由青光眼产生。 PI假设RC亚基的遗传变化导致受损线粒体呼吸，赋予了对RGC损失的敏感性增加，以及其他压力源（例如 IOP升高，表现为青光眼视神经神经病。具体目的将：1）确定眼在基线时和环境中的鼠模型中的表型和线粒体功能诱导眼高血压； 2）评估POAG患者的眼部表型和线粒体功能带有COI突变。通过优化RC功能评估的方法，这项研究有可能改变青光眼中细胞呼吸障碍的评估。将疾病风险与单倍型名称构成了个性化青光眼治疗迈出的重要一步。 PI将根据大学经验丰富的研究人员的指导进行研究宾夕法尼亚州（Upenn）和费城儿童医院。 Upenn是训练的理想场所临床医生科学家和Scheie眼科研究所是该国最好的研究者之一训练。眼科部致力于促进成功，并为PI提供了受保护的时间，专门的空间，机构资金和养育环境。 PI掌握了多个该提案中包括的技术，并制定了一项全面的职业发展计划，以促进个人成长。到K颁奖时期结束时，PI将获得成熟所需的知识进入独立研究者，将提高对青光眼的理解和治疗。