Grant: Operating Grant

Over four million of individuals are afflicted by different types of spinal cord injury (SCI). One of the consequences of SCI is the loss of neural tissue at the site of injury and the damage to neuronal projections that traverse the length of the spinal cord. Damage to these descending and ascending neuronal projections -termed axons- can result in loss of motor, sensory, and autonomic functions. Because the natural capacity of the mammalian central nervous system (CNS) to regenerate is extremely limited, unlike the peripheral nervous system (PNS), axonal damages sustained after SCI often lead to permanent functional deficits for which no cure is currently available. Among the many factors that prevent CNS neurons from regenerating their axons are molecules associated with degenerating myelin. Although these molecules are present in both the CNS and PNS, myelin-associated axon growth inhibitors are eliminated very rapidly by macrophages after peripheral nerve injury. In addition to remove myelin debris, macrophages release molecules that allow non-neuronal resident cells to switch into a growth-support mode. The direct result of this being the expression of trophic and guidance molecules for regenerating axons. In the human CNS, the macrophage response is deficient and can take up months to years to fully develop. The main goal of this research proposal is to identify the cellular and molecular mechanisms employed by macrophages to create a growth permissive environment for regenerating axons and utilized this knowledge to promote axonal regeneration in the injured CNS. Instructing immune cells to remove myelin and its inhibitors of axonal regeneration and provide adequate trophic support will have implications for regeneration following brain and spinal cord injury.