The role of impaired mitophagy and mitochondrial dysfunction in glaucomatous neurodegeneration

线粒体自噬受损和线粒体功能障碍在青光眼神经变性中的作用

• 批准号: 10284789
• 负责人: Prabhavathi Maddineni
• 金额: $ 9.94万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10284789
• 关键词: Advisory Committees; Autophagocytosis; Axon; Axonal Transport; Biological Assay; Blindness; Brain; Cell physiology; Cells; Chronic; Collaborations; Data; Demyelinations; Development; Electroretinography; Enhancers; Environment; Event; Eye; Failure; Genus Hippocampus; Glaucoma; Glucocorticoids; Goals; Health; Homeostasis; Human; Immune; Impairment; Inflammasome; Inflammatory; Institution; Knockout Mice; Laboratory Research; Learning; Measures; Mentors; Metformin; Mitochondria; Molecular; Monitor; Mus; Nerve Degeneration; Nerve Tissue; Neurodegenerative Disorders; Ocular Hypertension; Optic Nerve; PINK1 gene; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Pharmacology; Phase; Phenotype; Physiologic Intraocular Pressure; Primary Open Angle Glaucoma; Quality Control; Reporter; Research; Research Institute; Research Personnel; Retina; Retinal Ganglion Cells; Risk Factors; Role; Scientist; Stains; Structure; Synapses; TNF gene; TdT-Mediated dUTP Nick End Labeling Assay; Techniques; Texas; Therapeutic; Trabecular meshwork structure; Training; Transgenic Mice; Transgenic Organisms; Transmission Electron Microscopy; Visual; Visual evoked cortical potential; axon injury; axonal degeneration; base; career; career development; conditional knockout; cytokine; endoplasmic reticulum stress; experience; functional loss; human model; human tissue; improved; insight; meetings; mitochondrial dysfunction; mitochondrial metabolism; mouse model; myocilin; neuroinflammation; neuronal cell body; neurotransmission; novel; novel therapeutics; optic nerve disorder; overexpression; parkin gene/protein; prevent; symposium; therapeutic target; treatment strategy

PROJECT SUMMARY/ABSTRACT: Primary open angle glaucoma (POAG), the most common form of glaucoma, is characterized by progressive loss of retinal ganglion cells (RGCs) and their axons, leading to irreversible vision loss. Elevated intraocular pressure (IOP) is the major risk factor for POAG. Unfortunately, the underlying pathological mechanisms responsible for IOP-induced glaucomatous neurodegeneration still remain unclear. The long-term goal of this proposal is to delineate the molecular pathways governing IOP-induced glaucomatous neurodegeneration and to develop an effective glaucoma treatment strategy. To this end, we have developed a novel glucocorticoid (GC)-induced and myocilin-associated mouse models of POAG, replicating human POAG phenotypes. Importantly, we have identified impaired mitophagy, accumulation of damaged mitochondria and inflammatory immune cells in the optic nerve of both human and mouse glaucoma. Based upon our preliminary data, we propose to: 1) examine the effect of IOP on mitophagy impairment and accumulation of damaged mitochondria using mouse and human POAG, 2) examine the role of impaired mitophagy on glaucomatous neurodegeneration and, 3) further identify whether enhancing mitophagy alleviates neurodegeneration and prevent RGC loss in mouse models of POAG. In the mentored phase, I will establish mouse models to study mitophagy in POAG including mitophagy reporter transgenic Mt-Keima mice, RGC-specific Parkin and ATG5 conditional knockout mice under the guidance of Dr. Gulab Zode (an expert in chronic ER stress and autophagy in trabecular meshwork). In collaboration with Dr. Denise Inman (an expert in the field of mitochondrial metabolism), I will enhance my understanding of mitochondrial dysfunction in mouse models of POAG. The mentored phase will also be supplemented by training with Dr. Abbot Clark (well-known leading glaucoma expert), who will provide assistance with human tissues as well as an additional training for my independent career. Furthermore, regular meetings with Dr. Paula Gregory who has tremendous experience in assisting young investigators will help me to develop independent career. During the independent phase, we will examine role of mitophagy on inflammatory neurodegeneration and determine whether inducing mitophagy (Urolithin A/Actinonin/Metformin/ Parkin overexpression) rescues GC or myocilin-associated POAG. Additionally, during the mentored phase, I will be having regular meetings with my advisory committee, attend scientific conferences, and continue my career development. I am in the ideal environment for the proposed research and for my career development as Dr. Zode has an established state-of-the-art facilities at the North Texas Eye Research Institute, and collaborations with renowned scientists, Dr. Val Sheffield, Dr. John Hulleman and Dr. Kevin Park. This will help me to set-up good collaborations, learn new techniques, and build an independent research laboratory at a well- established academic institution.

项目总结/摘要： 原发性开角型青光眼（POAG）是最常见的青光眼形式，其特征在于进行性青光眼。 视网膜神经节细胞（RGC）及其轴突的丧失，导致不可逆的视力丧失。升高的眼内 眼压（IOP）是POAG的主要危险因素。不幸的是，潜在的病理机制 对IOP诱导的神经退行性变的作用机制仍不清楚。长期目标是 一项建议是描述控制IOP诱导的神经退行性疾病的分子途径， 开发有效的青光眼治疗策略。为此，我们开发了一种新型糖皮质激素 （GC）诱导的和肌球蛋白相关的POAG小鼠模型，复制人POAG表型。 重要的是，我们已经确定了受损的线粒体自噬，受损线粒体的积累和炎症反应。 免疫细胞在人类和小鼠青光眼的视神经中。根据初步数据，我们 拟：1）研究IOP对线粒体自噬损伤和受损线粒体累积的影响 使用小鼠和人POAG，2）检查线粒体自噬受损对青光眼神经退行性变的作用 和3）进一步确定增强线粒体自噬是否会减轻神经变性并防止RGC丢失， POAG小鼠模型。在指导阶段，我将建立小鼠模型来研究POAG的线粒体自噬 包括线粒体自噬报告基因转基因Mt-Keima小鼠、RGC-specific Parkin和ATG 5条件敲除小鼠 在Gulab Zode博士（小梁细胞慢性ER应激和自噬的专家）的指导下， 网状物）。在与丹尼斯·英曼博士（线粒体代谢领域的专家）的合作中，我将 增强了我对POAG小鼠模型中线粒体功能障碍的了解。指导阶段将 还可以通过Abbot Clark博士（著名的领先青光眼专家）的培训来补充，他将提供 协助人体组织以及为我的独立职业提供额外的培训。此外，定期 与Paula Gregory博士会面，他在帮助年轻研究人员方面有着丰富的经验，这对我很有帮助 发展独立的职业生涯。在独立阶段，我们将研究线粒体自噬在 炎症性神经变性和确定是否诱导线粒体自噬（尿石素A/肌动蛋白/代谢酶/ Parkin过表达）挽救GC或肌球蛋白相关的POAG。此外，在辅导阶段，我 我将定期与我的咨询委员会开会，参加科学会议，并继续我的工作。 职业发展。我在理想的环境中进行拟议的研究和我的职业发展， 博士Zode在北德克萨斯眼科研究所拥有成熟的最先进设施，并且 与著名科学家瓦尔谢菲尔德博士、约翰·胡尔曼博士和凯文·帕克博士合作。这将有助于 我建立良好的合作，学习新技术，并建立一个独立的研究实验室，在一个良好的- 建立学术机构。