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Project

Molecular control over motor circuit remodeling

Funder: Craig H Neilsen Foundation

Funding period
USD 300 K
Funding amount
Abstract
While the adult central nervous system (CNS) is not permissive for regeneration, studies using peripheral or embryonic CNS grafts have demonstrated that adult CNS neurons retain the ability to regenerate in the absence of inhibitory cues. One of these inhibitory cues, the axon guidance molecule ephrinB3, acts on descending corticospinal axons that express the receptor EphA4. EphrinB3 expression persists in both intact and injured adult spinal cord. This persistent expression makes ephrinB3-EphA4 signaling an attractive therapeutic target in the estimated 282,000 people living with chronic SCI (NSCISC, 2016). The overall objective for this proposal is to determine the effects of attenuating EphA4 signaling on corticospinal axon growth and motor network function after SCI. The central hypothesis is that conditional deletion of EphA4 in corticospinal neurons will increase axon regeneration after SCI, creating a novel circuit to restore skilled forelimb function. This hypothesis was formulated based on published findings demonstrating that the adult motor cortex can incorporate novel corticospinal connections formed after SCI and preliminary data indicating that conditional deletion of EphA4 promotes both corticospinal axon sprouting and recovery of corticospinal-dependent behavioral. Additionally, existing literature supports a role for EphA4 in limiting the growth and plasticity of corticospinal axons in response to inhibitory cues in the spinal cord. The rationale for the proposed research is that identification of the location and role of EphA4 signaling after SCI will allow for the subsequent development of strategies to target ephrin signaling as a treatment for motor dysfunction in acute and chronic 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

    2.1 Biological and endogenous factors

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Basic Science