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Project

Exofocal Injury after Spinal Cord Injury - the role of chronic microgliosis

Funder: Craig H Neilsen Foundation

Funding period
USD 296 K
Funding amount
Abstract
Recent data from patients after SCI has identified exofocal regions to undergo severe atrophy indicative of neurodegeneration. Neuropathological analysis (preliminary data) has uncovered evidence for oxidative burst, neuroaxonal dysfunction, and microglia/macrophage accumulation in lesion-remote areas after SCI. Lesion-remote areas of exofocal injury are localized in plasticity reservoirs essential for the recovery of neurological function. Exofocal injury in plasticity-relevant circuitry rostral and caudal to the lesion site can be considered a rate-limiting obstacle undercutting the intrinsic recovery potential after SCI. Aims 1 and 2 characterize exofocal injury with regards to i) cross species differences and ii) the presence of treatable underlying chronic immunopathology. Aim 3 applies two microglia modifying approaches (Plexxicon, PLX5622 and Fractalkine receptor (CX3CR1) depletion) to investigate the neuropathological impact of chronic microglia activation and accumulation on driving oxidative burst and damage, synaptic dysregulation and impaired axonal homeostasis in the inflamed spinal cord. Given that exofocal regions comprise circuitry essential for compensatory plasticity and successful rehabilitative therapy, neuronal injury in those regions will reduce the likelihood of exploiting neuroaxonal plasticity-induced functional gains, in line with a lowered rehabilitation responder rate. New targets to attenuate the emerging and dynamic exofocal injury are key to protect and maintain plasticity reservoirs and will be required for prolonged rehabilitating windows extending into chronic SCI.Collaborations include Dr. Phillip Popovich (OSU) to apply models of microglia depletion and deactivation, Dr. Dalton Dietrich (University of Miami) and Dr. Hans Lassmann and Dr. Roman Höftberger (University of Vienna) to cross-validate neuropathological findings across species in experimental animal models and chronic human 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