Glial metabolic status regulates axon regeneration in the central nervous system

神经胶质代谢状态调节中枢神经系统轴突再生

• 批准号: 10656678
• 负责人: Yuanquan Song
• 金额: $ 62.59万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656678
• 关键词: ATP Citrate (pro-S)-Lyase; Acute; Adult; Adverse effects; Afferent Neurons; Agonist; Astrocytes; Axon; Behavioral; Behavioral Assay; Binding; Binding Sites; Biological Assay; Cells; Central Nervous System; Chronic; Cicatrix; Citric Acid Cycle; Clinical; Corticospinal Tracts; Coupled; Coupling; Cyclic AMP; Data; Disease; Environment; Enzymes; Evolution; Exhibits; Functional Regeneration; GTP-Binding Proteins; Genes; Glycolysis; Goals; Growth; Guanine Nucleotides; Hypertrophy; Impairment; In Situ; Inflammatory; Injections; Injury; Knock-out; Lactate Dehydrogenase; Larva; Mammals; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molecular Target; Mus; Mutate; Natural regeneration; Nerve Regeneration; Nervous System Trauma; Neurodegenerative Disorders; Neuroglia; Neurologic Deficit; Neurons; Paralysed; Pathway interactions; Peripheral; Phase; Population; Production; Public Health; Publishing; Receptor Activation; Recovery; Recovery of Function; Refractory; Regenerative Medicine; Regenerative capacity; Reporting; Role; Sensory; Signal Transduction; Site; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Spinal cord injury; Stem cell transplant; Structure; Testing; Tissue Preservation; Translating; Up-Regulation; Work; axon injury; axon regeneration; central nervous system injury; data mining; differential expression; experimental study; fly; insight; mass spectrometric imaging; metabolomics; motor disorder; neonatal mice; neonate; nerve injury; nervous system disorder; neuron regeneration; novel; overexpression; pharmacologic; prevent; progenitor; receptor; receptor function; regenerative; regenerative therapy; repaired; response; targeted treatment; therapeutic target; transdifferentiation; translational potential

PROJECT SUMMARY Neuronal or axonal damage in the central nervous system (CNS), caused by injury or diseases, is irreversible and may lead to persistent neurological deficits. Spinal cord injury (SCI) often causes severe sensory and motor dysfunction and paralysis. Of approximately 1.9% of the U.S. population living with paralysis, over 1,275,000 are paralyzed as the result of SCI. Currently, there is still no cure for the injured spinal cord itself, emphasizing the desperate need to identify novel pathways for targeted therapy. Regarded as the holy grail in regenerative medicine, achieving axon regeneration and functional recovery after CNS injury or in neurodegenerative diseases remains a daunting task. The inability of CNS axons to regenerate after injury is attributed to the reduced intrinsic growth capacity of neurons and the inhibitory milieu largely constituted by the reactive glial cells. It is conventionally thought that the structural formation of glial scar and its upregulation of the repulsive CSPGs are the main culprit leading to stalled regrowth. However, accumulating evidence in the past decade has demonstrated that preventing astroglial scar formation following CNS injury does not result in increased regrowth. It is proposed that glial scar is important in preserving tissue integrity and mitigating further inflammatory damage. Glial scar may have beneficial effects during the acute phase of injury, but prevents axon regrowth in the chronic or later stages. In our latest work, via glia-specific metabolic reprogramming, we succeeded in mitigating their adverse effects while enriching their promotive functions. We demonstrated that glial reprogramming enhances glial glycolysis, and the production and release of metabolites – lactate and L-2HG, which act through neuronal GABABRs to boost axon regeneration. However, major gaps remain: are lactate and L-2HG the only pro-regeneration metabolites; do anti-regeneration metabolites also exist; do glia subtypes behave similarly after metabolic reprogramming. Our published work allows us to ask the essential question: does metabolic status dictate glia’s ability to promote or inhibit CNS axon regeneration? This would have a fundamental impact on our understanding of axon regeneration, as it applies to all species across the evolution spectrum. An equally intriguing question is: does the metabolic status differ between regeneration competent and incompetent CNS neurons? Our proposal aims to answer these questions, and test our hypothesis that glial and neuronal metabolic status governs the regeneration capacity of CNS neurons. Although various strategies to boost the neuronal intrinsic regenerative ability, to remove the extrinsic inhibitory factors such as CSPGs, to transdifferentiate glia into neurons, or to transplant stem cells into CNS have been reported, none of them have translated into clinical use. There is still a pressing need for new concepts to promote CNS axon regeneration. Our pilot results demonstrate that the state of glial cells that promotes axon regeneration can be achieved by reprogramming. This project aims to uncover metabolic enzymes as therapeutic targets, and metabolites or their derivatives as potential pharmacological agents for treating CNS injury.

项目概要 由损伤或疾病引起的中枢神经系统 (CNS) 神经元或轴突损伤是不可逆的 并可能导致持续性神经损伤（SCI），通常会导致严重的感觉和运动障碍。 大约 1.9% 的美国人口患有瘫痪，其中超过 1,275,000 人患有瘫痪。 因 SCI 导致瘫痪，目前尚无治愈脊髓损伤的方法。 迫切需要确定靶向治疗的新途径。 被视为再生医学的圣杯，术后实现轴突再生和功能恢复 中枢神经系统损伤或神经退行性疾病仍然是一项艰巨的任务中枢神经系统轴突无法再生。 损伤后的损伤主要归因于神经元内在生长能力和抑制环境的降低 传统上认为胶质疤痕的结构形成与其有关。 排斥性 CSPG 的上调是导致再生停滞的主要原因。 过去十年的证据表明，预防中枢神经系统损伤后星形胶质细胞疤痕的形成 不会导致再生增加，有人认为神经胶质疤痕对于保持组织完整性很重要。 减轻进一步的炎症损伤在损伤的急性期可能具有有益的作用， 但在我们最新的工作中，通过神经胶质细胞特异性代谢来阻止轴突的再生。 通过重新编程，我们成功地减轻了它们的不利影响，同时丰富了它们的促进功能。 证明神经胶质重编程增强神经胶质糖酵解以及代谢物的产生和释放 – 乳酸和 L-2HG，通过神经元 GABABR 发挥作用，促进轴突再生。 仍然：乳酸和 L-2HG 是唯一的促再生代谢物吗？还存在抗再生代谢物吗？ 代谢重编程后神经胶质亚型的行为是否相似？我们发表的工作让我们可以问： 基本问题：代谢状态是否决定神经胶质细胞促进或抑制中枢神经系统轴突再生的能力？ 将对我们对轴突再生的理解产生根本性影响，因为它适用于所有物种 一个同样有趣的问题是：再生之间的代谢状态是否有所不同。 有能力和无能力的 CNS 神经元？我们的提案旨在回答这些问题，并测试我们的能力。 假设神经胶质和神经元代谢状态控制中枢神经系统神经元的再生能力。 尽管有各种策略来增强神经元内在的再生能力，以消除外在的抑制 诸如CSPGs等因子，将神经胶质细胞转分化为神经元，或将干细胞移植到中枢神经系统中 据报道，它们都还没有转化为临床应用，仍然迫切需要新的概念。 促进中枢神经系统轴突再生。我们的试验结果表明，神经胶质细胞的状态可促进轴突再生。 再生可以通过重新编程来实现，该项目旨在揭示代谢酶的治疗作用。 靶点、代谢物或其衍生物作为治疗中枢神经系统损伤的潜在药物。