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Project

Metabolic reprograming of glial cells promotes axon regeneration in the CNS

Funder: Craig H Neilsen Foundation

Funding period
USD 300 K
Funding amount
Abstract
Neuronal or axonal damage in the central nervous system (CNS), caused by injury or disease, is irreversible and leads to persistent neurological deficits. Spinal cord injury (SCI) often causes severe sensory and motor dysfunction and paralysis, with no cure. Reduced neuronal intrinsic growth capacity and an inhibitory microenvironment contribute to the regeneration failure. After SCI, glial cells, in particular astrocytes, undergo reactive astrogliosis and form the glial scar that physically impedes regeneration, releasing inhibitory cues such as chondroitin sulfate proteoglycans (CSPGs). Although strategies to boost the neuronal intrinsic regenerative ability, to remove the extrinsic inhibitory factors, such as CSPGs, or to transdifferentiate glia into neurons have been proposed, there is still a pressing need for new concepts to promote CNS axon regeneration.Extensive efforts have been made trying to understand the extrinsic inhibitory cues including myelin associated inhibitors (MAIs), CSPGs, and the physical barrier constituted largely by the astrocytic scars. However, several studies have demonstrated that eliminating MAIs, or most recently, astrocytic scars does not allow significant axon regeneration in SCI models, challenging the glial scar dogma. It has been proposed that the formation of astrocytic scar may aid axon regeneration on the contrary. This is not so surprising if we ponder about the roles glia play during neurodevelopment. Glial cells have been shown to direct pathfinding and targeting of axons. Glial cells, in particular, astrocytes have emerged as key participants in neural circuit assembly, by controlling the formation, maturation and function of synapses. More intriguingly, immature astrocytes can support the regeneration of adult central axons, suggesting that there is a specific state in which glial cells are capable of promoting axon regeneration. We hypothesize that glial cells including the scar forming astrocytes can be reprogrammed into this state, and that we are able to harvest their stimulating effects while at the same time ameliorating the adverse side effects of scaring.Our exciting results demonstrated that the state of glial cells that promotes axon regeneration can be achieved indeed by reprogramming, namely by expressing specific combination of genes in glial cells. We found that glial-reprogramming-induced metabolic rewiring, reverses glial inhibition of axon regeneration in the CNS, via increased glycolysis and the glycolysis associated metabolites. Elucidating the mechanism how the glia-derived metabolites in the microenvironment regulate neuroregeneration will also provide valuable insights to the essential question, why axons in the mammalian CNS are unable to regenerate, and offer novel disease treatment options. Specifically, we have already identified metabolic enzymes as new gene therapy targets, and metabolites or their derivatives as potential pharmacological agents for treating SCI. (CHN: SCIRTS chn:wdg)
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System

Categories
  • FOR (ANZSRC)

    1109 Neurosciences

  • RCDC

    Injury (total) Accidents/Adverse Effects

  • RCDC

    Injury - Trauma - (Head and Spine)

  • RCDC

    Regenerative Medicine

  • RCDC

    Neurosciences

  • RCDC

    Spinal Cord Injury

  • RCDC

    Neurodegenerative

  • HRCS HC

    Neurological

  • HRCS RAC

    1.1 Normal biological development and functioning

  • HRCS RAC

    2.1 Biological and endogenous factors

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Basic Science