Our goal is to advance the understanding of genetic epilepsies using tractable model systems. Epilepsy is one of the most common neurological problems known to humans, affecting several percent of the US and world population. Anticonvulsant drugs are used to treat many individuals, but these agents can be toxic and their side effects severe. If the causes of epilepsy were defined more precisely, it would be possible to devise better therapeutic approaches. At least one third of all epilepsies have no obvious etiology, and many are suspected to have a genetic basis. The advantage of studying genetic epilepsies is that primary defects can be pinpointed unambiguously and examined as targets for therapy. Finding such defects will also unravel the relationship between various physiological changes that accompany seizure. Genetic studies of human epilepsy are progressing, but obstacles such as clinical heterogeneity and small family size remain difficult to overcome. However, there are several tractable laboratory model systems. the murine """"""""EL"""""""" model closely resembles the most common genetic epilepsies, where several genes combined to produce recurrent, generalized seizures. In addition, a previously-untapped model, """"""""SWXL- 4"""""""", is phenotypically very similar to EL but has a distinct genealogic origin. By utilizing recently-developed molecular genetic tools for analyzing genetic traits, we will identify epilepsy genes and determine how they combine with each other to cause generalized seizures. Our approach will be: (i) to identify all the significant genetic factors that cause seizures in the EL model, (ii) to determine the precise chromosomal location of several of these genes and genetically reconstruct the model to learn each gene's contribution to the phenotype, (iii) to clone and find the molecular defect for at least one of these genes, and (iv) to begin dissecting the genetic basis of epilepsy in the new, SWXL-4 model. These efforts will lead to a better understanding of how multiple genes combined to cause complex neurogenetic disorders, and will provide specific clues for studying human epilepsy. It will also be possible to identify specific genetic markers that can be tested for linkage with human epilepsies.
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