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.

项目总结