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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.!

这项研究将测试中心假设，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-R76 E，通过以下途径保护视网膜神经节细胞（RGC）免受青光眼发病机制的影响：直接激活这些细胞中的Nrf 2通路。已知氧化应激显著促进青光眼发病机制EPO可以通过激活Nrf 2信号传导来降低氧化应激，从而导致抗氧化反应元件（ARE）的抗氧化蛋白表达增加。我们将测试 1）确定EPO-R76 E如何影响Nrf 2信号传导 2）比较RGCs、星形胶质细胞和Müller细胞中EPO-R76 E诱导的Nrf 2途径活化;以及 3)测量EPO-R76 E诱导的信号传导和EPO-R76 E微粒在非人免疫细胞中的功效。青光眼的灵长类动物模型。我们将在两个物种中使用青光眼的微珠阻塞模型。我们将利用遗传学和药理学方法来确定激活的途径和相对的星形胶质细胞、Müller细胞和RGCs在EPO-R76 E诱导的Nrf 2/ARE活化中的贡献。我们将使用细胞类型特异性重组腺相关病毒和启动子，途径抑制剂，流式细胞术，和显微镜。最后，我们将测试负载有EPO-R76 E的固有抗氧化剂微粒的功效在临床相关的物种松鼠猴身上。我们希望能对青光眼有更深入的了解致病机制，从而确定可药用的目标。此外，我们希望证明EPO- R76 E微粒是一种安全有效的青光眼非IOP依赖性治疗方法。