Targeting Endogenous Inhibitors to Enhance Spinal Axon Regeneration After Injury

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DESCRIPTION (provided by applicant): Spinal cord injury typically results in life-long loss of nerve function accompanied by profound morbidity and mortality. The current project will use a well-established animal model for human spinal cord injury - spinal cord contusion in the rat - to investigate novel ways to enhance recovery. Our approach is based on our recent discovery that delivery of the enzyme sialidase to the site of experimental spinal cord injuries results in significant enhancements in spinal axon outgrowth, locomotor recovery, and cardiovascular reflex recovery. We now propose to quantify a battery of behavioral, neurophysiological and neuroanatomical outcomes to explore the potential of sialidase, alone and in combination with other treatments, to enhance recovery after spinal cord injury. Our proposal is based on a wealth of data indicating that central nervous system axons have the capacity to regenerate, but are inhibited from doing so by endogenous axon regeneration inhibitors (ARI's), including myelin-associated glycoprotein (MAG), Nogo, and oligodendrocyte-myelin glycoprotein on residual myelin and chondroitin sulfate proteoglycan (CSPG) on the glial scar. Each ARI binds to complementary receptors on axons, halting axon outgrowth. Knowledge of ARI's and ARI receptors provides new opportunities to block ARI actions and enhance recovery. For example, the enzyme sialidase destroys sialoglycans, a class of ARI receptors for MAG, and the enzyme chondroitinase ABC (ChABC) destroys CSPG. Anti-ARI therapies, individually or in combination, may enhance axon regeneration and improve functional recovery after spinal cord injury. We now propose to: (i) Test the hypothesis that sialidase delivery to the site of a spinal cord contusion injury in the rat will enhance axon plasticity and/or regeneration, resulting in significant functional recovery; (ii) Test the hypothesis that combining independent anti-ARI therapies, such as sialidase and ChABC, will result in additive or synergistic enhancements of recovery after spinal cord contusion injury, and (iii) Use our knowledge of sialoglycans and sialidases to identify the molecular target(s) of therapeutic sialidase and discover the best sialidase(s) for preclinical studies. PUBLIC HEALTH RELEVANCE: The mature central nervous system, including the spinal cord, is overwhelmingly inhibitory for axon regeneration, severely limiting recovery after traumatic injury and resulting in life-long loss of function. Remarkably, axons have the ability to regenerate, but are inhibited from doing so by molecules that accumulate at injury sites. Destroying or blocking these molecules may permit axons to regenerate, greatly enhancing functional recovery.