Role of the Nrf2/ARE pathway in retinal ganglion cells during glaucoma pathogenesis and neuroprotection

Nrf2/ARE 通路在青光眼发病机制和神经保护中视网膜神经节细胞中的作用

• 批准号: 10291073
• 负责人: David J. Calkins
• 金额: $ 5.96万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10291073
• 关键词: Abate; Age; Antioxidants; Automobile Driving; Axon; Binding; Blindness; Brain; Cell Nucleus; Cessation of life; Chronic; Data; Development; Disease; Disease Progression; Erythropoietin; Event; Fellowship; Gene Expression; Genes; Genetic Transcription; Glaucoma; Goals; Hypertension; Injury; Intervention Studies; Investigation; Knockout Mice; Measures; Mediating; Medical; Mentors; Messenger RNA; Microspheres; Modeling; Mus; Mutate; NF-E2-related factor 2; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Nuclear Translocation; Ocular Hypertension; Operative Surgical Procedures; Optic Nerve; Optics; Oxidative Stress; Parents; Pathogenesis; Pathway interactions; Patients; Phosphorylation; Physiologic Intraocular Pressure; Postdoctoral Fellow; Proteins; Reactive Oxygen Species; Reporting; Research Personnel; Response Elements; Retina; Retinal Ganglion Cells; Risk Factors; Role; Safety; Scientist; Signal Transduction; Signaling Protein; Superoxides; Testing; Therapeutic; Time; Treatment Efficacy; Ubiquitin; Vision; axonal degeneration; base; biological adaptation to stress; cell type; druggable target; gene therapy; inhibitor/antagonist; insight; modifiable risk; neuroinflammation; neuroprotection; new therapeutic target; overexpression; oxidation; preservation; protein expression; response; retinal ganglion cell degeneration; success; therapeutically effective; transcription factor

Project Summary Glaucoma is the world's leading cause of irreversible vision loss. The only modifiable risk factor for glaucoma is intraocular pressure (IOP) and thus all existing medical and surgical approaches target the IOP. Unfortunately, many patients continue to lose vision despite IOP management. Glaucoma involves progressive degeneration of retinal ganglion cells (RGCs), whose axons form the optic projection from retina to brain. Thus, our long-term goal is to develop new treatments to abate this neurodegeneration directly in an IOP- independent manner, based on identification and targeting of critical mechanisms of disease progression. We previously reported that erythropoietin or a mutated version of it, EPO-R76E, are able to preserve the RGCs in models of glaucoma. Our data shows that it modulates neuroinflammation and increases expression of antioxidant proteins. In our parent R01, we propose to use gene therapy strategies in the microbead occlusion model to determine the role of NRF2 and the antioxidant response element in EPO-R76E-mediated neuroprotection in glia and RGCs, separately, in glaucoma. In this supplement application, we propose to expand the scope of investigation to explore the endogenous response of the retina and RGCs to hypertension-induced oxidative stress. The anticipated significant accomplishment of this proposal is identification of new druggable targets early in glaucoma pathogenesis and clarity on the cell types to target, which will increase the safety and efficacy of treatments. It also provides an unique opportunity for Sarah Naguib to be mentored into an independent vision researcher poised for a successful post-doctoral fellowship.

项目摘要 青光眼是世界上最主要的不可逆视力丧失的原因。唯一可以改变的风险因素 青光眼是眼内压（IOP），因此所有现有的医疗和手术方法都以IOP为目标。 不幸的是，尽管IOP管理，许多患者仍继续丧失视力。青光眼涉及进行性 视网膜神经节细胞（RGC）变性，其轴突形成从视网膜到脑的视投射。因此，在本发明中， 我们的长期目标是开发新的治疗方法，直接在IOP中减轻这种神经变性， 独立的方式，基于疾病进展的关键机制的识别和靶向。我们 先前报道，促红细胞生成素或其突变形式EPO-R76 E能够在 青光眼模型。我们的数据表明，它调节神经炎症，并增加 抗氧化蛋白在我们的亲本R 01中，我们建议在微珠闭塞中使用基因治疗策略 模型来确定NRF 2和抗氧化反应元件在EPO-R76 E介导的 分别在青光眼中的神经胶质细胞和RGCs中的神经保护作用。在本补充申请中，我们建议 扩大研究范围，探索视网膜和RGC对 高血压引起氧化应激。这一提议的预期重大成果是 在青光眼发病机制的早期鉴定新的可药物靶点和明确靶向的细胞类型， 这将增加治疗的安全性和有效性。这也为莎拉提供了一个独特的机会 纳吉布将被指导成为一个独立的视觉研究人员准备一个成功的博士后奖学金。