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

基本信息

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
项目类别：
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

项目摘要

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不可逆转的视力丧失的主要原因。唯一可修改的风险因素青光眼是眼内压（IOP），因此所有现有的医学和外科手术方法都针对IOP。不幸的是，尽管有IOP管理，许多患者仍继续失去视力。青光眼涉及进行性视网膜神经节细胞（RGC）的变性，其轴突从视网膜到脑形成了视力投影。因此，我们的长期目标是开发新的治疗方法，直接在IOP中减轻这种神经退行性。基于鉴定和靶向疾病进展的关键机制的独立方式。我们以前报道说，促红细胞生成素或IT突变版本EPO-R76E能够保存RGC 青光眼模型。我们的数据表明，它调节神经炎症并增加了抗氧化剂蛋白。在我们的父r01中，我们建议在Microbead闭塞中使用基因治疗策略确定NRF2和抗氧化剂响应元件在EPO-R76E介导的模型神经保护胶质和RGC中的神经保护作用，分别是青光眼中的神经保护作用。在此补充申请中，我们建议扩大调查范围，以探索视网膜和RGC对的内源性反应高血压诱导的氧化应激。该提议的预期重大成就是在青光眼的发病机理中鉴定出新的可药靶标的细胞类型的明确性，这将提高治疗的安全性和功效。它还为莎拉提供了独特的机会纳吉布将被指导成一个有望成功的博士后奖学金的独立愿景研究员。