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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

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.

项目总结