Grant: Project Grant

Spinal cord injury leads to severe and permanent paralysis. One major reason for paralysis is that, when injured, long-projecting corticospinal axons fail to regenerate, which permanently interrupts communication between the brain with the rest of the body. Unfortunately, no regenerative therapy is available to individuals following spinal cord injury today, making such a treatment a critical unmet need of the Canadian healthcare system. Corticospinal neurons have a remarkable ability to regenerate during early development but lose this ability as they mature. Our data suggests that a major intracellular process governing this loss of regenerative ability is Calcium-dependent vesicle release. This process is the major function of mature neurons integrated in synaptic circuits as it enables these cells to communicate with one another, but we have evidence that it prevents regeneration by stabilizing the axon in a way that prevents its re-growth. Excitingly, if we dampen Calcium-dependent vesicle release using a clinically available drug called Baclofen, we can revitalize the corticospinal neuron's ability to regrow axons, which would be of tremendous therapeutic value in a clinical setting. In this project, we will address how Calcium-dependent vesicle release suppresses corticospinal axon regeneration and examine the capacity of Baclofen treatment to restore corticospinal-dependent functions following spinal cord injury. This work will greatly expand our knowledge of how neurons lose the ability to regenerate during development. More importantly, we think that the outcomes of this project will provide practical information on how Baclofen, which is currently clinically available and used on a case-by-case basis to treat muscle spasticity, can be rationally repurposed as a regenerative treatment for spinal cord injury and potentially other diseases and disorders.