|
Mapping of synaptic connectivity between descending neurons and mammalian spinal interneurons using photostimulation and optical recording.
Funded for two years; $150,000. Truly an international effort: The lead investigators are Joel Glover, an American, and Marie- Claude Perreault, a Canadian, both professors at the University of Oslo. Two graduate students funded by the grant are from Norway and Hungary.
If it is possible to regrow a nerve, is it then possible for that nerve to make the correct connection? Surprisingly little is known about whether nerve fibers (axons) regrowing from the brain make appropriate connections. This innovative basic science project hopes to describe how growing axons hook up with specific populations of lumbar spinal interneurons in mammals. Until this is understood the concept of regeneration is missing a key element.
A great deal of research effort in the past two decades has been focused on finding ways to promote regrowth of the severed axons. However, regrowth is not a complete solution, because to regain function the nerve fibers that regrow must also connect with the proper target nerve cells in the spinal cord. Therefore, information about how descending fibers normally connect to spinal interneurons (which make up most of the functional circuitry in the spinal cord) is crucial for designing strategies for promoting regeneration or compensation following spinal cord injuries.
Mapping the connections on to spinal interneurons has been very difficult because the classical techniques for identifying and characterizing the connections have been inefficient and tedious. The key to the project is the use of state-of-art photostimulation, functional imaging and electrophysiology to follow growing axons and map them as they connect with spinal nerves. The experiments will provide much new information about the way the brain connects to the spinal cord normally, and will set the stage for doing similarly rapid analyses of the correctness of connections made after nerve fibers regrow after a spinal cord injury.
Non-hormonal gender differences in SCI and sulfonylurea therapy.
Funded for two years, total $150,000. Principle investigator: J. Marc Simard, M.D., Ph.D., University of Maryland School of Medicine, Neurosurgery.
This project proposes to run a set of animal experiments to treat acute spinal cord injury with a drug that has in previous studies limited the damage of trauma. The drug has been widely used for many years to treat diabetes. Dr. Simard, a neurosurgeon, also wants to show why males with SCI have poorer outcomes than females, unrelated to hormones.
Several years ago Dr. Simard's lab discovered a type of ion channel in the injured spinal cord (called SUR1-regulated NCCa-ATP) that is related to cell death due to cellular bleeding in the minutes and hours after trauma. His team also found a way to block the channel's action with a drug called glibenclamide (glyburide). When given soon after severe cervical injury, this resulted in a "striking reduction in hemorrhage and improvement in functional outcome," says Dr. Simard.
This proposal will test glibenclamide at various times after injury in an animal model of SCI to see if delayed treatment (at two and four hours after trauma) retains the benefit observed when treatment starts without delay. If the drug is effective, it could lead to human clinical trials. Dr. Simard and his team also want to confirm the existence of non-hormonal gender differences in a cervical injury model while demonstrating the specific role of SUR1.
Work from other laboratories has shown that injury severity and outcome post-SCI are gender-related, with gender differences attributable in part to hormonal influences. Says Dr. Simard, new work from his laboratory has shown that in response to brain or spinal cord injury, SUR1 is found in greater amounts in males than in females.
Simard is encouraged by recent clinical experience with glibenclamide. The outcome from stroke in humans was found to be significantly improved in patients with diabetes mellitus who were taking glibenclamide and who continued on it during their hospitalization for stroke. Coincidentally, SUR1 affects production of insulin; when blocked by glibenclamide, insulin output increases, thus improving diabetes symptoms.
Dr. Simard recently treated a 17-yearold patient who came to the hospital with a rapid onset of paralysis. He had no sensation or movement. MRI showed a blood clot crushing his spinal cord. Dr. Simard gave him glibenclamide and removed the clot. Soon after the patient was able to move both legs. Less than a month later, the patient was wobbly, but walking.
"This kind of dramatic recovery was very unusual," says Dr. Simard. "I don't want to overstate the case but this shows, I believe, a benefit from our animal studies. Of course we need proper clinical trials to know. Before human trials can begin, however, it is necessary to show in animals that delayed treatment post-SCI is effective in improving outcome. The experiments proposed here are designed, in part, to address this important issue."
|
