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Erythropoietin-mediated antioxidant pathways in glaucoma

青光眼中促红细胞生成素介导的抗氧化途径

基本信息

批准号：
10414846
负责人：
David J. Calkins
金额：
$ 5.78万
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 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10414846
关键词：
Abate Antioxidants Astrocytes Attenuated Automobile Driving Axon Axonal Transport Blindness Brain Cell Death Cells Chronic Clinical Treatment Dangerousness Disease Elements Erythropoiesis Erythropoietin Eye Flow Cytometry Gene Delivery Genetic Glaucoma Goals Histology Inflammatory Legal patent MAPK3 gene MAPK8 gene Measures Mediating Microscopy Microspheres Modeling Molecular Monkeys Muller&apos s cell Mus NF-E2-related factor 2 Nerve Degeneration Neuroglia Nuclear Translocation Operative Surgical Procedures Optic Disk Optic Nerve Optics Outcome Measure Oxidative Stress Pathogenesis Pathway interactions Patients Pharmacology Phosphorylation Physiologic Intraocular Pressure Property Proteins Publishing Reactive Oxygen Species Recombinant adeno-associated virus (rAAV)Reporter Response Elements Retina Retinal Ganglion Cells Rodent Saimiri Signal Pathway Signal Transduction Stress Structure Testing Therapeutic Treatment Efficacy Viral Viral Vector Vision antioxidant enzyme base cell type cellular targeting clinical translation clinically relevant cytokine druggable target efficacy testing experimental study inhibitor/antagonist insight mutant neuroinflammation neuroprotection nonhuman primate novel p38 Mitogen Activated Protein Kinase pre-clinical preservation prevent promoter protein expression response retinal ganglion cell degeneration

项目摘要

This study will test the central hypothesis that our patented, minimally erythropoietic, form of erythropoietin (EPO), EPO-R76E, protects retinal ganglion cells (RGCs) from glaucoma pathogenesis by directly activating the Nrf2 pathway in these cells. Oxidative stress is known to contribute significantly to glaucoma pathogenesis. EPO can decrease oxidative stress through activation of Nrf2 signaling to result in increased expression of antioxidant proteins from the antioxidant response element (ARE). We will test our hypothesis through the following Specific Aims: 1) Determine how EPO-R76E influences the Nrf2 signaling pathway; 2) Compare EPO-R76E-induced Nrf2 pathway activation in RGCs, astrocytes, and Müller cells; and 3) Measure EPO-R76E induced signaling and the efficacy of EPO-R76E microparticles in a non-human primate model of glaucoma. We will use the microbead occlusion model of glaucoma in both species. We will utilize genetic and pharmacological approaches to determine the pathways activated and the relative contributions of astrocytes, Müller cells, and RGCs in EPO-R76E induced Nrf2/ARE activation. We will use cell-type specific recombinant adeno-associated viruses and promoters, pathway inhibitors, flow cytometry, and microscopy. Finally, we will test the efficacy of inherently-antioxidant microparticle loaded with EPO-R76E in a clinically relevant species, the squirrel monkey. We expect to gain greater insight into glaucoma pathogenesis leading to the identification of druggable targets. Further, we expect to demonstrate that EPO- R76E microparticles are a safe and effective IOP-independent treatment for glaucoma.!

这项研究将检验中心假设，我们的专利，最低限度的红细胞生成，形式促红细胞生成素(EPO)，EPO-R76E，通过以下途径保护视网膜神经节细胞(RGCs)免受青光眼的影响直接激活这些细胞中的Nrf2途径。众所周知，氧化应激在很大程度上导致青光眼发病机制。促红细胞生成素可通过激活Nrf2信号导致氧化应激减轻来自抗氧化反应元件(ARE)的抗氧化蛋白表达增加。我们将测试我们的假设通过以下具体目的：1)确定EPO-R76E如何影响Nrf2信号 2)比较EPO-R76E诱导的视网膜神经节细胞、星形胶质细胞和Müller细胞中Nrf2通路的激活； 3)检测EPO-R76E诱导的信号转导及EPO-R76E微粒在非人类体内的作用青光眼的灵长类模型。我们将在两个物种中使用青光眼的微珠阻塞模型。我们会利用遗传学和药理学方法来确定激活的通路和相关的星形胶质细胞、Müler细胞和视网膜节细胞在EPO-R76E诱导的Nrf2/ARE激活中的作用我们将使用细胞类型特异性重组腺相关病毒和启动子，途径抑制物，流式细胞术，和显微镜。最后，我们将测试负载EPO-R76E的天然抗氧化剂微粒的效果在临床相关物种中，松鼠猴。我们希望对青光眼有更深入的了解致病机制导致确定可用药的靶点。此外，我们希望证明EPO- R76E微粒是一种安全有效的非眼压青光眼治疗方法。