Epilepsy is a common debilitating neurologic condition that can be partially treated, but not cured with current medications. The goal of this project is to identify cellular and molecular changes that contribute to the development of epilepsy after an injury to the brain. We will induce a long seizure called status epilepticus (SE) to induce the development of epilepsy or spontaneous seizures. The process by which a person or animal becomes epileptic is called epileptogensis. The CREB family of transcription factors CREB, CREM and ICER bind to a consensus sequence of DNA called CRE (cyclic-amp response element) sites, and then activate or inhibit transcription of a large number of genes. We have found that SE increases the active forms of CREB and ICER and that mutants that lack the CREM/ICER gene develop more severe epilepsy following SE. Here we propose to use transgenic mice with alterations in CREB, CREM and ICER to determine if these transcription factors are necessary for the development of epilepsy following SE. We will also determine if blocking CREB activity can suppress seizures once they develop or even reverse epileptogensis. To better understand the mechanism by which CRE mediated transcription influences epileptogensis we will determine the role of CREB, CREM, and ICER in gene transcription following SE. There are hundreds of genes that contain CRE sites in their promoter regions. There however is limited knowledge about which genes that contain CRE sites in their promoter are regulated by CREB, CREM and ICER after SE. Here we propose to utilize the transgenic mice to determine which changes in gene expression following SE are CREB and CREM/ICER dependant. By understanding which gene changes after SE are CRE dependent, we can begin to identify the molecular cascade that contributes to the development of epilepsy after brain injury. These changes in gene transcription also provide therapeutic targets for the development of epilepsy after brain injury. The proposed experiments will contribute to understanding how an insult to the brain leads to the development of spontaneous seizure and what treatment strategies might be useful to prevent the development of epilepsy.

Public Health Relevance

The proposed grant will study a group of regulatory proteins that are increased in animal epilepsy models and in patients with epilepsy. We will determine if blocking the increase in the regulatory proteins protects the animals from the development of epilepsy. In addition we will determine which genes these proteins regulate in epilepsy.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroscience and Disease Study Section (CND)
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Stewart, Randall R
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Children's Hospital of Philadelphia
United States
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