Grant: Project Grant

Spinal cord injury disconnects the brain from parts of the body below the injury, resulting in paralysis, abnormal pain and bladder dysfunction. Unfortunately, treatments to repair the injured spinal cord are still lacking. However, we recently made the unexpected discovery that blood flow is permanently reduced in the entire spinal cord below an injury, suggesting that improving blood flow offers a new approach to treating injury. We found that this low blood flow is caused by an exaggerated activity in specialized cells called pericytes that act like valves on small blood vessels. This then leads to insufficient blood flow and ultimately loss of residual functions like walking. We find that transiently blocking this exaggerated pericyte activity, or supplying oxygen, temporarily promotes recovery of walking in animal models. This is the basis for our current proposal, where we ask three questions. First, how do we best apply treatments to more permanently restore blood flow and oxygen to the spinal cord, and are these treatments safe (e.g. does not enhance abnormal pain)? Second, what causes the excessive pericyte activity following spinal cord injury, and can it be prevented? We have convincing preliminary data that indicate that a lack of activity in the neurons below a spinal cord injury triggers the excessive pericyte activity, since daily nerve stimulation to excite the spinal cord over the first few weeks after spinal cord injury restores normal pericyte function, eliminates hypoxia and markedly improves residual movement. If proven correct, this idea opens up new clinically applicable treatments to restore blood flow, including electrical nerve stimulation and rehabilitation training that promote neuronal activity early after injury. Lastly, we explore whether humans with spinal cord injury also suffer from a lack of oxygen in the spinal cord below the injury and whether restoring blood flow promotes recovery in sensory and motor function.