Status epilepticus is associated with significant long-term morbidity, including intellectual impairment, focal neurologic dysfunction, and recurrent seizures. Part of this morbidity is related to the neuronal injury resulting from prolonged, excessive electrical activity. Although various lines of evidence suggest that excitatory amino acids and their receptors are important mediators of seizure-induced injury, very little is known about the cellular defense against this excitotoxic injury. The central theme of the proposed research plan is to explore the relationship between stress protein (SP) expression and protection from seizure-induced neuronal injury. The overall hypothesis is that heat-shock proteins and other stress proteins are expressed by CNS cells in response to prolonged seizures, and that this expression is part of the cell's protective mechanism against excitotoxic injury. There are two major goals of the proposed research. The first is to characterize the scope, temporal sequence, and cellular location of stress proteins induced by prolonged seizures within the hippocampus. Two well-characterized in vivo models of seizures will be used, and SP expression will be analyzed via one and two-dimensional polyacrylamide gel electrophoresis, immunoblotting, and immunocytochemistry. The second goal is to use cell culture systems to determine whether stress proteins protect CNS cells against toxic factors, such as excitatory amino acids, that may be involved in the pathogenesis of seizure-induced neuronal damage. SP expression (induced by traditional methods and by exposure to excitatory amino acids) will first be characterized in primary cultures of rat neurons and glia. Various approaches will then be used to modulate the activity of SPs, in order to determine whether there is a causal relationship between SP expression and protection of CNS cells. The research training is designed to build upon the applicant's expertise in the clinical aspects of status epilepticus, and his fellowship training in molecular biology. Upon completion of the program, he will have obtained the experience and background necessary to develop an independent research program investigating the pathophysiology of status epilepticus at the molecular level.
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