Grant: Operating Grant - PA: Regional Partnership Program - Saskatchewan

Sensory neurons relay information between our body and our spinal cord and brain via peripheral nerves. When these nerves are injured, they induce an intrinsic repair response we have shown is critically dependent on brain-derived neurotrophic factor (BDNF), whose expression is regulated by neuronal activity. But, regeneration of these nerves is still fraught with challenges that result in incomplete repair and/or pain states. We have identified a therapeutic intervention, brief electrical nerve stimulation at the time of repair, that increases BDNF expression and results in much more robust and accurate repair. Even the axonal electrical discharge at the time of injury, we find is critical to inducing the intrinsic neuronal repair state. But, the underlying early cell and molecular mechanisms linking increased neuronal activity and BDNF to induction of a more robust intrinsic regeneration state are largely unknown and the focus of our research, as they may provide novel therapeutic targets. The early injury-induced/activity-regulated events that we hypothesize contribute and/or are critical to a robust regenerative state include rapid activity-induced alterations in membrane responsiveness to local neurotrophin cues; increased expression of an activity-regulated cytoskeleton protein we believe is critical to forming the growth cone a component of the growing axon front; and a novel axon-localized transcription factor that we hypothesize serves as an important retrograde injury signal to the sensory neuron to regulate regeneration-associated transcriptional events and help the neuron cope with injury-associated stressors. Finally, we will employ nerve stimulation strategies to determine if they can also improve regeneration of peripheral nerves where repair is delayed, a clinically challenging scenario. We believe that learning how to optimally manipulate the intrinsic repair programs in sensory neurons will vastly improve nerve repair outcomes for Canadians.