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Project

Novel chemical approaches for specific targeting of CSPGs to restore function after SCI

Funder: Craig H Neilsen Foundation

Funding period
USD 600 K
Funding amount
Abstract
Spinal cord injury (SCI) is a devastating condition, currently affecting 288,000 people in the United States. Injury to the spinal cord leads to neuronal and glial cell death, axon loss, and inflammation at the site of injury. This is followed by inhibition of tissue regeneration and functional loss. Despite this, there are no approved regenerative or disease modifying therapies for promoting tissue repair and restoring connectivity. In this proposal, we will build on novel discoveries in our laboratory that indicate key roles for chondroitin sulfate (CS) glycosaminoglycans (GAGs) and their associated proteoglycans (CSPGs) in the regulation of axonal regeneration and neuroplasticity. CSPGs are up-regulated in the glial scar after injury and inhibit axon regeneration. This inhibitory activity is known to be predominantly derived from their CS chains. Although CSPGs have traditionally been viewed as non-specific barriers to neuronal growth, our research indicates that specific sulfation patterns on CS chains can also interact with neuronal receptors, such as EphA4 of PTPs, and activate key signaling pathways important for axon regeneration, sprouting, and neuroplasticity. In particular, the CS-E motif inhibits the re-growth of sensory neurons after injury, is up-regulated in PNNs and the glial scar, and binds the receptor for advanced glycation end product (RAGE), which is important in modulating inflammation following injury. Building on these fundamental findings, we aim to develop novel CS-E blocking agents that will prevent CSPG inhibition, enhance axonal outgrowth, and lead to improved functional outcome after SCI. We propose to develop a single-chain variable fragment antibody against CS-E (CS-E scFv) and a panel of selective, potent inhibitors for Chst15, the N-acetylgalactosamine 4-sulfate-6-O-sulfotransferase responsible for the biosynthesis of CS-E. We will validate these two complementary therapeutic approaches in vitro using a microfluidics axotomy assay and organotypic spinal cord slice cultures, before translating the most promising therapeutics to in vivo rodent SCI contusion models. This highly innovative proposal will enhance our current understanding of the mechanisms underlying SCI, and should lead to the development of new, promising SCI treatments, as envisioned by the Neilson Foundation. (CHN: SCIRTS chn:wdg)
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System

Categories
  • FOR (ANZSRC)

    0601 Biochemistry and Cell Biology

  • FOR (ANZSRC)

    1109 Neurosciences

  • RCDC

    Injury (total) Accidents/Adverse Effects

  • RCDC

    Injury - Trauma - (Head and Spine)

  • RCDC

    Biotechnology

  • 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

    5.1 Pharmaceuticals

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Basic Science