Therapeutic effects of ketogenic diet in a mouse model of severe myoclinic epilep

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I am a young neuroscientist with a graduate training from the University of Tennessee and postdoctoral training from the University of Washington. I have acquired solid knowledge in the principles of neuroscience and excellent technical expertise centered on dissociated cell and brain slice electrophysiology. My long term career goals are to establish a research lab, as an independent investigator, focused on understanding and developing cures for neurological disorders. In addition, I expect to teach and train health professionals and scientists. To attain these goals, I intend to dedicate the 3-5 year award period of this grant toward expanding my scientific knowledge and enhancing research skills. The scientific activities of this proposal will include participating in seminars, journal clubs, national and international meetings; preparing manuscripts for publication; and training students and junior post-doctoral fellows. The research activities will include learning novel techniques for me including recording brain activity in live animals by electroencephalography (EEC), culturing cells and expressing ion channels, and making gene mutations. I will use these techniques to intensively investigate the therapeutic properties of ketogenic diet in severe myoclonic epilepsy in infancy (SMEI, as known as Dravet syndrome) using a mouse model of the disorder at the University of Washington, one of the leading research institutions in the nation. SMEI is a very malignant form of childhood epilepsy that has been associated recently with mutations causing reduced type 1 sodium (Nay 1.1) channels. These mutations are found in Scnla, the gene encoding av 1.1 channels, they prevent channel expression or reduce function. A mouse model of SMEI was created in our lab by introducing mutations that prevent Scnla gene expression. These mutant mice have reduced Nav 1.1 sodium current and reproduce the main clinical features of human SMEI including severe seizures and ataxia. Human SMEI seizures are not well-controlled with most anti epileptic drugs. Ketogenic diet is a calorie restricted regimen that provides a ratio of fat to carbohydrate and protein combined of about 4:1. This diet is often more efficacious in managing difficult-to-control seizures such as those in SMEI. However, the mechanisms responsible for its antiepileptic efficacy are not understood. The research proposed has the following specific aims : 1) To determine the anticonvulsive and antiepileptic effects of ketogenic diet in mouse SMEI; 2) to evaluate changes in neuronal function and sodium channel expression underlying the therapeutic effects of ketogenic diet; 3) to investigate the effects of ketogenic diet on the function of 'brain' voltage-gated sodium channels. RELEVANCE (Seeinstructions): These studies will advance the understanding of the mechanisms of action of ketogenic diet by revealing its impacts on Nav channel expression and function as well as on neuron excitability and seizure susceptibility. Furthermore, this study will give new insights that may help in the design of future pharmacological- or non-pharmacological therapies for SMEI and other epilepsy syndrome refractory to current antiepileptic drugs.