The objective of this project is to develop potential approaches to the therapy of brain and spinal cord injury. One approach is to limit the production or increase the degradation of chondroitin sulfate proteoglycans. We have developed a viral vector that targets a key enzyme in the chondroitin sulfate synthetic pathway and have supplied this vector to our collaborator for testing in animal models of spinal cord injury. We have determined that the viral vector (which is tagged with a fluorescent protein marker) is expressed after injection into the uninjured mouse central nervous system. Current experiments are demonstrating expression after a contusion injury to the mouse spinal cord and also evaluating effects on axonal growth and sprouting and behavioral recovery of function. We have published studies that demonstrate significant changes in the regulation of CSPGs in response to controlled cortical impact traumatic brain injury. These studies show that TBI causes astrogliosis and an increase in the production of CSPGs in the gliotic area, but also reduces CSPGs in preirneuronal nets. We are conducting studies to understand the changes in cell motility and ECM formation in fibroblasts derived from patients with mutations in chondroitin sulfotransferases. We hope to develop techniques to restore normal function to these fibroblasts.
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