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Project

Age-dependent decline of axon growth via reduction of SOCS3/STAT3 signaling

Funder: Craig H Neilsen Foundation

Funding period
USD 300 K
Funding amount
Abstract
Spinal cord injury has seen a dramatic change in its demographic population in the past decades and is no longer considered as a “young” disease. Not only the average age of incidence increased from ~29 to ~43 today, but ~80% of SCI-paralyzed patients are over 40. Despite these changes, our understanding of how age can impact injury, repair and recovery is extremely limited. Indeed, most studies are performed in young adult animals, which do not correspond to the human population. This dichotomy will impede any clinical translation. We recently showed an age-dependent decline in axon growth, as regenerative interventions exhibit reduced efficacy when performed on 12months old mice (~40years in humans). This was mediated, in part, by changes in astroglial and inflammatory responses at the injury site. Our data now suggest that age also modulates the neuronal molecular signaling. Indeed, after unilateral pyramidotomy of the cortico-spinal tract, neuronal PTEN deletion enhances axonal sprouting in an age-independent manner, even when deletion occurs weeks after injury. However, SOCS3 deletion, which activates the STAT3 pathway, exhibited a stark decline in promoting axon growth with age. While neonatal PTEN/SOCS3 co-deletion synergistically promotes sprouting and induces functional recovery, this beneficial effect was no longer observed in young adults, suggesting that age differentially impacts neuronal signaling pathways. STAT3 signaling is also involved in mitochondrial function, which is necessary for axon growth but is also known to be reduced with age. Therefore, we hypothesize that changes in the STAT3 pathway occurring with age reduce axonal growth, via reduction of transcriptional and mitochondrial activity. We hope to demonstrate that increasing the STAT3 signaling and/or mitochondrial activity will stimulate axon growth regardless of age, enhance the age-independent effect of PTEN deletion and ultimately promote functional recovery irrespective of age. (CHN: SCIRTS chn:wdg)
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System

Categories
  • FOR (ANZSRC)

    1109 Neurosciences

  • RCDC

    Aging

  • RCDC

    Injury (total) Accidents/Adverse Effects

  • RCDC

    Injury - Trauma - (Head and Spine)

  • RCDC

    Neurosciences

  • RCDC

    Rehabilitation

  • RCDC

    Spinal Cord Injury

  • RCDC

    Neurodegenerative

  • HRCS HC

    Neurological

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Basic Science