Using integrin receptors to study in vivo mechanisms of spinal cord repair Event

Abstract: Following traumatic injury, the adult central nervous system (CNS) does not regenerate. Successful removal of inhibitory proteins within the lesion site alone is not sufficient to induce long distance repair of damaged axons. Additionally, damaged neurons within the mature CNS lack many of the growth-promoting molecules that are necessary for self-repair. One effective strategy we have utilised is forced expression of integrin receptors, specifically alpha9 integrin, the receptor for the main extracellular matrix glycoprotein of the CNS, tenascin-C, which we have found to stimulate axonal growth following a dorsal root and dorsal spinal injury. This growth was minimal however with two obstacles restricting significant growth; inactivation of integrins and restriction of integrin localisation to the somatodendritic compartment rather than the axonal compartment. We have modified this strategy to incorporate combined integrin expression with intracellular activation to overcome lesion-induced inactivation in dorsal column sensory axons resulting in long distance axonal regrowth and functional recovery. Furthermore, our studies have shown that axonal localisation of integrins is dependent on both neuronal subtype and age whereas within motor axons there is an inability of these neurons to transport these receptors into their axons. Future strategies we are pursuing with respect to stimulating neuronal growth within the corticospinal tract involve: 1) forced expression of integrins in mice with a conditional deletion of PTEN; and 2) implanting stem cells that overexpress growth-promoting molecules to recapitulate the developing nervous system and its regenerative ability.