Acute damage to the central nervous system due to stroke, seizure disorders, and trauma are very common, and these problems are the most frequent neurologic causes of death and disability. It has been thought that several pathological molecular mechanisms are present in all of these disorders. In the past there have been few attempts to systematically study these precise relationships in a coordinated fashion. Previously, much attention was focussed on abnormalities of energy metabolism and blood flow. There can be little doubt that these factors are of considerable importance, but it is probable that they are not the sole causes of irreversible damage and play a relatively minor part in whatever recovery of function occurs. Our contention is that there are rapid alterations in protein structure and function in response to acute CNS insults that are critical to maintenance and restoration of neurologic integrity. Consequently, we have designed a program to investigate the similarities and differences in degenerative and regenerative responses to a variety of acute neurological insults. We will use 4 types of systems to model CNS injury: 1) surgical lesions in the fimbria-fornix pathway; 2) a seizure model produced by a lesion in this same area; 3) in vivo ischemia models; 4) a tissue culture ischemia model. The studies will consist of detailed examinations of the changes in protein phosphorylation, molecular genetics, and growth factors that occur a times of interest after the injury. We will also correlate physiological, histological, and behavioral alterations during the degenerative and recovery phases. Finally, we will use these initial observations to help us develop a framework for selection of therapies with transplants or pharmacological agents.
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