Genetic factors play a key regulatory role in the development of hereditary and acquired epilepsies such as temporal lobe epilepsy. The host response to neural injury involving axonal sprouting and aberrant synapse formation, appears to be under tight regulatory control at the genome level having functional implications for epileptogenesis. The objective of this proposal is to identify transcriptional regulatory proteins responsible for morphologic alterations of neural circuitry and use molecular genetic approaches to elucidate the molecular basis of synaptic reorganization. Evidence has been obtained that transcriptional mechanisms can account for susceptibility of seizure sensitive mouse strains to kainic acid induced neural injury and epileptogenesis. This project focuses on the regulation of synaptic organization and the role the transcription factor NRSF/REST plays in this process. Dr. Greg Barnes, a recently recruited M.D/Ph.D. will conduct the research. The project involves a study of the regulation of the NRSF/REST gene in a kainic acid-induced model of epilepsy where synaptic remodeling occurs. The three specific aims are: 1)To distinguish between differences in the REST/NRSF gene and differences in REST regulatory proteins as the cause of susceptibility to Kainic Acid Status Epilepticus induced neural injury; 2)To characterize regulatory complexes associated with the REST/NRSF promoters following Kainic Acid Status Epilepticus; 3) Test differentially expressed regulatory proteins identified in Aim 2 in the mediation of kainic acid-induced synaptic reorganization and epileptogenesis. Differences in either the nucleotide sequence of the NRSF/REST gene or expression of transcription factors that regulate this gene are proposed to account for differences in susceptibility to kainic acid-induced status epilepticus between different mouse strains. Dr. Barnes will utilize the proteomics and tissue culture cores of the COBRE grant in this project. These studies are designed to provide new insights into regulation of the NRSF/REST gene, its involvement in regulating synaptic reorganization, and its role in epilepsy.
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