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Understanding the Etiology of Tuberous Sclerosis Complex
Annual rept. 1 Jul 2011-30 Jun 2012
YALE UNIV NEW HAVEN CT
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Tuberous Sclerosis Complex TSC is a genetic multisystem disorder characterized by severe neurological symptoms e.g. seizures, which are the most significant causes of disability and morbidity. Presently, there are no known cures for TSC and the etiology of the disease is not well understood, perhaps due to the lack of model system to study this disorder. In TSC patients, mutations in Tsc1 or Tsc2, result in the formation of lesions. The mechanisms leading to TSC lesions and associated seizure generation during perinatal life remain unclear in the absence of an animal model of TSC lesions. The goal of our recent ongoing funding cycle based on our Statement of Work was to generate TSC lesions using a new approach in transgenic Tsc1 mice Task 1 and to assess at which developmental stages some of the defects start to occur following Tsc1 inactivation Task 2. These two Tasks have been achieved in due time as proposed in our Timeline. Using a novel technical approach i.e. in vivo electroporation in mice with conditional and mutant alleles we generated the first TSC animal model that replicates the discrete cortical lesions seen in humans. We have gathered information on the mechanisms of lesion formation and cortical hyperexcitability. This latter work is undergoing. We have published our findings in a research article and have also published a News and Views regarding this article. We have presented our data at several meetings.
APPROVED FOR PUBLIC RELEASE