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

项目摘要 青光眼是世界上导致不可逆转视力丧失的主要原因。唯一可修改的风险因素是 青光眼是眼压(IOP)，因此所有现有的内科和外科方法都是针对眼压的。 不幸的是，尽管进行了眼压管理，许多患者仍继续失明。青光眼涉及进行性青光眼 视网膜神经节细胞(RGC)变性，其轴突形成从视网膜到大脑的视觉投射。因此， 我们的长期目标是开发新的治疗方法，以减轻眼压直接导致的神经变性- 以确定和确定疾病发展的关键机制为基础的独立方式。我们 先前报道，促红细胞生成素或其突变版本EPO-R76E能够保护RGC在 青光眼模型。我们的数据显示，它调节神经炎症并增加 抗氧化蛋白质。在我们的亲代R01中，我们建议使用基因治疗策略来治疗微球闭塞 确定NRF2和抗氧化反应元件在EPO-R76E介导中作用的模型 在青光眼中，神经胶质细胞和视网膜节细胞的神经保护。在本补充申请中，我们建议 扩大调查范围，探索视网膜和视网膜节细胞对 高血压引起的氧化应激。这项提议预期取得的重大成就是 在青光眼发病机制早期识别新的可用药靶点，并明确靶点的细胞类型 这将增加治疗的安全性和有效性。这也为萨拉提供了一个独特的机会 纳吉布将被指导成为一名独立的视力研究员，为成功的博士后奖学金做好准备。

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.