NGFN-PLUS

Functional analysis of human ion channel mutations in cellular and animal models

Coordinator:    Prof. Dr. Holger Lerche
Institution: Neurologische Klinik des Universitätsklinikums Ulm
Homepage: www.uniklinik-ulm.de/struktur
Pharmacoresistance and side effects of anti-epileptic drugs (AEDs) represent serious problems in epilepsy treatment. With identification of the synaptic vesicle protein SV2A as high-affinity binding site for the AED Levetiracetam (LEV), the presynapse has come into focus as a target for AEDs. For many patients, LEV would be a promising AED, but serious behavioral side effects occur in up to 8% of LEV-treated patients, resulting in discontinuation of treatment. Here, we will study the genetic basis for pharmacoresistance and behavioral side effects of LEV and analyze the function of SV2A in epilepsy. Our main objectives are: sequence analysis of the SV2A gene with regard to LEV pharmacoresponse; genome-wide search for relevant genetic factors involved in LEV pharmacoresistance and behavioral side effects; analysis if LEV pharmacoresistance is due to a decreased binding of LEV to SV2A; study of the correlation between pharmacoresistance and hippocampal SV2A expression; analysis of the role of SV2A in epileptogenesis, seizure generation or suppression. Our studies might reveal novel targets for drug development and more therapy- and cost-effective perspectives for epilepsy patients.
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