Glial metabolic status regulates axon regeneration in the central nervous system

项目摘要 中枢神经系统（CNS）中的神经元或轴突损伤是由损伤或疾病引起的，是不可逆的 并可能导致持续的神经缺陷。脊髓损伤（SCI）通常会导致严重的感觉和运动障碍， 功能障碍和瘫痪。在大约1.9%的美国瘫痪人口中，超过1，275，000人 因SCI而瘫痪。目前，仍然没有治愈受伤的脊髓本身，强调 迫切需要确定新的靶向治疗途径。 被誉为再生医学的圣杯，在移植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。中枢神经系统轴突不能再生 损伤后神经元的生长抑制主要是由于神经元内在生长能力的降低和抑制环境的改变 由反应性神经胶质细胞组成。传统上认为胶质瘢痕的结构形成及其 排斥性CSPG的上调是导致再生长停滞的主要原因。然而，积累 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形成 不会导致再生增加。有人提出，胶质瘢痕是重要的，在保持组织的完整性， 减轻进一步的炎症损伤。神经胶质瘢痕在损伤的急性期可能具有有益的作用， 但在慢性或后期阶段阻止轴突再生。在我们最新的工作中，通过胶质细胞特异性代谢 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。我们 表明神经胶质细胞重编程增强了神经胶质细胞的糖酵解，以及代谢产物的产生和释放 - 乳酸和L-2 HG，其通过神经元GABABR起作用以促进轴突再生。然而，主要差距 剩余：乳酸和L-2 HG是唯一的促再生代谢物吗？是否也存在抗再生代谢物？ 神经胶质亚型在代谢重编程后是否表现相似。我们发表的工作使我们能够问 一个基本问题：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？这 将对我们对轴突再生的理解产生根本性的影响，因为它适用于所有物种， 进化光谱一个同样有趣的问题是： 中枢神经系统神经元的功能我们的建议旨在回答这些问题，并测试我们的 神经胶质和神经元代谢状态控制CNS神经元再生能力的假说。 尽管有各种策略来增强神经元内在的再生能力，去除外在的抑制性因子， 例如CSPG，将神经胶质转分化为神经元，或将干细胞移植到CNS中的因素已经被 据报道，它们都没有转化为临床使用。仍然迫切需要新的概念， 促进CNS轴突再生。我们的试验结果表明，促进轴突生长的神经胶质细胞的状态 再生可以通过重编程来实现。该项目旨在揭示代谢酶作为治疗 靶点，以及作为治疗CNS损伤的潜在药理学试剂的代谢物或其衍生物。

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.