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

• 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
• 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

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.

项目总结 视神经炎是多发性硬化(MS)最常见的临床表现之一。它会导致严重的 视神经炎症性脱髓鞘(ON)引起的视力丧失 视网膜神经节细胞(RGC)。临床上对神经保护剂的重大需求未得到满足是因为缺乏 了解触发神经退行性级联反应的关键上游信号。我们之前的研究 结果表明，急性和慢性损伤均可诱导视网膜节细胞内质网应激。我们 如果我们通过以下方式阻断内质网应激的有害影响，我们就能够保护受损的RGC胞体和轴突 以相反的方式操纵未折叠蛋白反应(UPR)的两个关键下游分子：a) CCAAT/增强子结合蛋白同源蛋白(CHOP)的缺失，和/或b)X-box结合的激活 蛋白1(XBP-1)。因此，轴突损伤诱导的内质网应激可能是神经元损伤的一种常见机制。 靶向神经元内质网应激在疾病中可能具有相当大的治疗性神经保护潜力 与轴索病有关。大鼠实验性自身免疫性脑脊髓炎模型的建立 髓鞘蛋白免疫可复制MS的许多临床症状和病理体征，包括 视神经炎和显著的RGC胞体和轴突丢失。已在白质和灰质中检测到内质应激 在多发性硬化症患者的大脑和EAE小鼠身上。我们证实了神经元内质网应激在自身免疫诱导中的作用 EAE的神经退行性变。此外，最近对轴突沃勒变性的令人兴奋的研究表明 参与轴突NAD+代谢的几个关键分子在轴突变性中起关键作用。Sarm1 例如，(不育Alpha和TIR基序1)受轴突NAD+合成酶的负调控 烟酰胺单核苷酸腺基转移酶2(NMNA2)诱导轴突变性；缺失 Sarm1或轴突NMNAs的激活导致轴突保护。在这里，我们建议检验这一假设 同时调节神经元内质网应激和NAD+代谢将协同防止两者 EAE/视神经炎中RGC胞体和轴突的变性和视力保护。我们预计这将是 研究将明确确定新的治疗靶点，我们的发现最终将被翻译成 为多发性硬化症和视神经炎患者安全地进行创新的神经保护治疗。