Epileptic seizures can cause progressive neurodegeneration and cognitive impairment in patients independent of episodes of status epilepticus. Using a novel mouse model of focally-evoked seizures with EEG quantification we have isolated the electrographic (EEG) signature of injury-causing seizures from seizures that are tolerance-inducing. Second, we have identified a preeminent role for the 14-3-3 family of molecular chaperone proteins in the coordination of cell death pathways after seizures and we demonstrate that interaction with 14-3-3 is a potent predictive tool for identifying novel mediators of injury following seizures. The hypothesis to be tested is: injury-producing seizures and seizures that confer protection against injury evoke unique genomic fingerprints which encode novel proteins that interact with the 14-3-3 family of cell death regulators, thus yielding new target regulators of the balance of cell death and survival after seizures. The specific aims are: 1) By contrasting the genomic response of hippocampal neurons from animals subject to injury-producing seizures with the response following non-injury producing seizures and seizures that confer tolerance against injury-producing seizures we will identify specific genetic markers that predict outcome following seizures; 2) To use 14-3-3 proteins as a focused functional screen to identify among the regulated genes those most relevant to the control of seizure-induced cell death. Our laboratory is focused on understanding the relationship between seizures, brain damage and the cell death pathways that underlie neurodegeneration in epilepsy patients. Our focused application of DNA microarrays to isolate the genomic fingerprint of specific epileptic seizures provides us with a new tool in the pursuit of this goal; combining this with a function-based screening tool (interaction with 14-3-3 proteins) will establish a new approach placing microarray data into a useable context. This R21 proposal has significant practical applications; the data will establish a cohort of cell death-regulating genes in the context of identifiable seizure types, endowing us with new insight into the consequences and treatment of those seizures resulting in brain injury.

R21NS046290

2004-06-01

2006-12-31