Developing Novel Neuroprotective Strategies for EAE/Optic Neuritis

开发针对 EAE/视神经炎的新型神经保护策略

基本信息

批准号：
10200056
负责人：
Yang Hu
金额：
$ 45.54万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10200056
关键词：
Acute Address Anatomy Autoimmune Axon Binding Proteins Biological Assay Blindness Brain C57BL/6 Mouse CCAAT-Enhancer-Binding Proteins Candidate Disease Gene Cell Nucleus Cells Chromatin Chronic Clinical Clinical Trials Combined Modality Therapy Crush Injury Demyelinations Dependovirus Disease Dissociation Electroretinography Experimental Autoimmune Encephalomyelitis Genome Glaucoma Goals Homologous Protein Immunization In Situ Individual Inflammation Inflammatory Inherited Intervention Knockout Mice Lead Maps Mediating Metabolism Modeling Molecular Morphology Multiple Sclerosis Mus Myelin Proteins Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurons Neuroprotective Agents Nicotinamide-Nucleotide Adenylyltransferase Optic Nerve Optic Nerve Injuries Optic Neuritis Pathogenesis Pathologic Pattern Proteins Regulatory Element Retina Retinal Diseases Retinal Ganglion Cells RiboTag Ribosomes Rodent Role Signal Transduction Sterility Symptoms Techniques Testing Therapeutic Tissues Transcript Translating Transposase Vision Visual Visual evoked cortical potential Wallerian Degeneration adeno-associated viral vector axon injury axonal degeneration axonopathy chronic neurologic disease clinical translation clinically relevant combinatorial efficacy testing endoplasmic reticulum stress experience experimental study functional outcomes gene therapy genetic manipulation gray matter immunomodulatory therapies improved injured innovation mouse myelin oligodendrocyte glycoprotein multiple disability multiple sclerosis patient neuronal cell body neuroprotection new therapeutic target novel preservation prevent promoter response retinal axon retinal ganglion cell degeneration synthetic enzyme therapeutic target therapy development translatome white matter young adult

Acute Address Anatomy Autoimmune Axon Binding Proteins Biological Assay Blindness Brain C57BL/6 Mouse CCAAT-Enhancer-Binding Proteins Candidate Disease Gene Cell Nucleus Cells Chromatin Chronic Clinical Clinical Trials Combined Modality Therapy Crush Injury Demyelinations Dependovirus Disease Dissociation Electroretinography Experimental Autoimmune Encephalomyelitis Genome Glaucoma Goals Homologous Protein Immunization In Situ Individual Inflammation Inflammatory Inherited Intervention Knockout Mice Lead Maps Mediating Metabolism Modeling Molecular Morphology Multiple Sclerosis Mus Myelin Proteins Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurons Neuroprotective Agents Nicotinamide-Nucleotide Adenylyltransferase Optic Nerve Optic Nerve Injuries Optic Neuritis Pathogenesis Pathologic Pattern Proteins Regulatory Element Retina Retinal Diseases Retinal Ganglion Cells RiboTag Ribosomes Rodent Role Signal Transduction Sterility Symptoms Techniques Testing Therapeutic Tissues Transcript Translating Transposase Vision Visual Visual evoked cortical potential Wallerian Degeneration adeno-associated viral vector axon injury axonal degeneration axonopathy chronic neurologic disease clinical translation clinically relevant combinatorial efficacy testing endoplasmic reticulum stress experience experimental study functional outcomes gene therapy genetic manipulation gray matter immunomodulatory therapies improved injured innovation mouse myelin oligodendrocyte glycoprotein multiple disability multiple sclerosis patient neuronal cell body neuroprotection new therapeutic target novel preservation prevent promoter response retinal axon retinal ganglion cell degeneration synthetic enzyme therapeutic target therapy development translatome white matter young adult

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项目摘要

PROJECT SUMMARY Optic neuritis is one of the most common clinical manifestations of Multiple Sclerosis (MS). It causes severe visual loss due to inflammatory demyelination of the optic nerve (ON) and subsequent degeneration of ON and retinal ganglion cells (RGCs). The significant unmet clinical need for neuroprotectants is due to the lack of understanding of the key upstream signals that trigger the neurodegenerative cascade. Our previous studies demonstrated that both acute and chronic ON injury induce endoplasmic reticulum (ER) stress in RGCs. We were able to protect the injured RGC soma and axons if we blocked the detrimental effects of ER stress by manipulating two key downstream molecules of the unfolded protein response (UPR) in opposite ways: a) deletion of CCAAT/enhancer binding protein homologous protein (CHOP), and/or b) activation of X-box binding protein 1 (XBP-1). Thus axon injury-induced ER stress may be a common mechanism of neuronal damage and targeting neuronal ER stress may have considerable therapeutic neuroprotective potential in diseases associated with axonopathy. The rodent experimental autoimmune encephalomyelitis (EAE) model induced by immunization with myelin proteins replicates many clinical symptoms and pathological signs of MS, including optic neuritis and significant RGC soma and axon loss. ER stress has been detected in white and grey matter of MS patients' brains and in EAE mice. We confirmed the role of neuronal ER stress in autoimmune-induced neurodegeneration in EAE. Furthermore, exciting recent studies of axonal Wallerian degeneration have shown that several key molecules involved in axonal NAD+ metabolism are critical for axonal degeneration. SARM1 (Sterile Alpha and TIR Motif 1), for example, is negatively regulated by axonal NAD+ synthetic enzyme nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) to induce axon degeneration; deletion of SARM1 or activation of axonal NMNATs results in axon protection. Here we propose to test the hypothesis that modulating both intrinsic neuronal ER stress and NAD+ metabolism will synergistically prevent both RGC soma and axon (ON) degeneration and preserve vision in EAE/optic neuritis. We anticipate that this study will unambiguously identify novel therapeutic targets and that our findings will ultimately be translated safely into innovative neuroprotective treatments for patients with MS and optic neuritis.

项目摘要视神经炎是多发性硬化症（MS）最常见的临床表现之一。它会导致严重视觉神经的炎症性脱髓鞘引起的视觉丧失（ON）以及随后的ON和ON变性视网膜神经节细胞（RGC）。神经保护剂的显着未满足的临床需求是由于缺乏了解触发神经退行性级联的关键上游信号。我们以前的研究证明急性和慢性损伤都会诱导RGC中的内质网（ER）应激。我们如果我们通过阻塞ER应力的有害影响，能够保护受伤的RGC SOMA和轴突以相反的方式操纵展开的蛋白质反应（UPR）的两个关键下游分子：a）删除CCAAT/增强剂结合蛋白同源蛋白（CHOP）和/或B）X-Box结合的激活蛋白1（XBP-1）。因此，轴突损伤引起的ER应力可能是神经元损伤的常见机制，靶向神经元素胁迫可能在疾病中具有相当大的治疗性神经保护潜力与轴突病有关。啮齿动物实验性自身免疫性脑脊髓炎（EAE）模型由用髓磷脂蛋白免疫复制MS的许多临床症状和病理体征，包括视神经炎和明显的RGC SOMA和轴突丧失。在白色和灰色物质中检测到ER压力 MS患者的大脑和EAE小鼠。我们证实了神经元ER应力在自身免疫性诱导的 EAE中的神经变性。此外，令人兴奋的轴突沃勒变性的研究表明轴突NAD+代谢中涉及的几个关键分子对于轴突变性至关重要。 SARM1 （无菌α和TIR基序1），例如，由轴突NAD+合成酶负调节烟酰胺单核苷酸腺苷转移酶2（NMNAT2）诱导轴突变性；删除 SARM1或轴突NMNAT的激活会导致轴突保护。在这里，我们建议检验以下假设调节固有的神经元ER应力和NAD+代谢都将协同阻止两者 RGC SOMA和AXON（ON）变性并保留EAE/视神经炎的视觉。我们预料到了研究将明确识别新的治疗靶标，我们的发现最终将被翻译安全地进入MS和视神经炎患者的创新神经保护治疗。