Glial metabolic status regulates axon regeneration in the central nervous system

项目总结 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 并可能导致持续的神经缺陷。脊髓损伤常导致严重的感觉和运动。 功能障碍和瘫痪。在美国约1.9%的瘫痪人口中，超过1275,000人 由于脊髓损伤而瘫痪。目前，受伤的脊髓本身仍然没有治愈的方法，强调 迫切需要找到靶向治疗的新途径。 被视为再生医学的圣杯，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 损伤后神经元的内在生长能力下降和抑制环境在很大程度上是造成的 由反应性胶质细胞构成。传统认为，胶质瘢痕的结构形成及其与其关系密切。 排斥性CSPG的上调是导致再生停滞的主要原因。然而，积累起来 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瘢痕的形成 不会导致更多的再生。有人认为，胶质瘢痕在保护组织完整性和 减轻进一步的炎症损害。在损伤的急性期，胶质瘢痕可能会有有益的影响， 但在慢性期或后期会阻止轴突再生。在我们最新的工作中，通过胶质细胞特有的代谢 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 证明了胶质细胞重新编程增强了神经胶质糖酵解，以及代谢物的产生和释放 -乳酸和L-2HG，它们通过神经元GABA受体促进轴突再生。然而，主要差距是 残留：乳酸和L-2HG是仅有的促再生代谢物吗；是否也存在抗再生代谢物； 在新陈代谢重新编程后，胶质细胞亚型的表现是否类似。我们出版的作品让我们可以问 基本问题：新陈代谢状态是否决定了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 会对我们理解轴突再生产生根本性的影响，因为它适用于所有物种 进化谱。一个同样耐人寻味的问题是：再生和再生之间的代谢状态是否不同 有能力和无能力的中枢神经系统神经元？我们的提案旨在回答这些问题，并测试我们的 神经胶质和神经元代谢状态支配中枢神经系统神经元再生能力的假说。 虽然有各种策略来增强神经元的内在再生能力，但要消除外在的抑制 CSPGs，将神经胶质细胞转化为神经元，或将干细胞移植到中枢神经系统等因素一直是 据报道，这些药物都没有转化为临床使用。仍然迫切需要新的概念来 促进中枢神经系统轴突再生。我们的实验结果表明，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具有治疗作用。 作为治疗中枢神经系统损伤的潜在药理药物的靶点、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.