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.

项目摘要 受伤或疾病引起的中枢神经系统（CNS）中的神经元或轴突损伤是不可逆的 并可能导致持续的神经系统缺陷。脊髓损伤（SCI）通常会引起严重的感觉和运动 功能障碍和麻痹。大约1.9％的美国人口瘫痪，超过1,275,000 SCI的结果瘫痪。目前，仍无法治愈受伤的脊髓本身，强调 迫切需要确定针对性治疗的新途径。 被视为再生医学中的圣杯，在 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 受伤后，归因于神经元和抑制​​环境的内在生长能力降低。 由反应性神经胶质细胞组成。通常认为神经胶质疤痕及其的结构形成 排斥CSPG的上调是导致遗憾停滞的主要罪魁祸首。但是，积累 过去十年中的证据表明，CNS受伤后防止星形胶质疤痕形成 不会导致改革增加。有人提出，神经胶质疤痕在保持组织完整性和 减轻进一步的炎症损害。神经胶质疤痕在急性损伤期内可能具有有益的作用， 但是可以防止慢性或更高阶段的轴突改革。在我们的最新作品中，通过Glia特异性代谢 重新编程，我们成功地减轻了他们的不良影响，同时富含其晋升功能。我们 证明神经胶质重编程可增强神经胶质糖酵解，并产生和释放代谢物 - 乳酸和L-2HG，通过神经元Gababrs起作用以增强轴突再生。但是，主要差距 剩余：是鞋底和L-2HG是唯一的促进代谢物；也存在抗再生代谢物； 代谢重编程后，请胶质亚型的表现类似。我们发表的工作使我们能够问 基本问题：代谢状态是否决定了Glia促进或抑制CNS轴突再生的能力？这 将对我们对轴突再生的理解产生根本性的影响，因为它适用于各地的所有物种 进化频谱。同样有趣的问题是：再生之间的代谢状态差异是否存在 胜任和无能的CNS神经元？我们的建议旨在回答这些问题，并测试我们 神经胶质和神经元代谢状态控制CNS神经元的再生能力的假设。 尽管各种策略来增强神经元内固有的再生能力，但可以消除外部抑制作用 诸如CSPG，将神经胶质分解为神经元或移植干细胞中的因素已经是 报道说，它们都没有转化为临床用途。仍然需要新概念来 促进CNS轴突再生。我们的试点结果表明，促进轴突的神经胶质细胞状态 可以通过重新编程来实现再生。该项目旨在发现代谢酶作为治疗 靶标，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。