The inability of CNS axons to regenerate and reinnnervate appropriate targets after trauma results in chronic compromise of function, which presents a devastating prognosis for TBI, MS, stroke and SCI patients. Myriad studies have identified two broad classes of axon growth inhibitor (AGI) proteins responsible for axon growth arrest, the myelin associated inhibitors (Nogo, MAG, OMgp) and the Chondroitin Sulfate Proteoglycans (CSPGs). Experimental paradigms that negate the activity of these inhibitors in vivo have shown a slight increase in regeneration of damaged axons, but a more dramatic restitution of function. Before therapeutic options move into the clinic it is necessary to define the mechanism whereby anti-AGI strategies restore function. An alternative hypothesis to long distance regeneration-mediated restitution of function would be the reorganization of intact spinal circuitry that often remains after SCI. It is the central goal of this proposal to comprehensively evaluate the potential for intact spinal circuits to replace lost connections, and furthermore define whether negating the action of AGIs supports adaptive or maladaptive axonal reorganization. Using a combination of anatomical, electrophysiological, genetic and in vivo imaging methodology we plan to delineate the plastic potential of intact spinal circuitry. The Neurology department at Yale is inimitably positioned to facilitate these studies owing to its world-class faculty and the availability of cutting-edge core facilities, including multi-photon in vivo imaging technology and mouse transgenesis facilities. The continued training in molecular and cellular biology have I have received at Yale as a postdoctoral associate has uniquely complimented the whole-animal physiology skills that I mastered during my PhD at King's College London, UK. Under the earnest supervision of Prof. Stephen Strittmatter, it is my immediate goal to apply these potent skills to answering some of the fundamental questions that remain in the field of CNS axon regeneration, such as; is long distance regeneration necessary for recapitulation of function? Is the adult CNS under tonic growth inhibition due to the continued expression of inhibitor proteins? Furthermore is the adult CNS wired with contingent plans for plasticity in case of injury? In the long-term it is my overall goal to initiate an independent research lab and continue pursing my ultimate goal of assisting in the design of therapeutic strategies for SCI patients. In summary, we plan to use anatomical, electrophysiological, genetic and in vivo imaging methodology to define the extent of plasticity within intact spinal circuitry and investigate the capacity of de novo circuits to restore function after spinal cord and therefore reduce the burden of this neurological disease borne by every age group, by every segment of society, by people all over the world.
