Tuberous Sclerosis Complex (TSC) is one of the most common genetic causes of epilepsy. In addition, epilepsy in TSC is typically very severe and intractable to available therapies. Most current treatments for epilepsy are simply symptomatic therapies that may suppress seizures but do not necessarily correct the underlying brain abnormalities causing the epilepsy. Thus, understanding the brain mechanisms causing epilepsy ("epileptogenesis") is necessary to develop more effective, "anti-epileptogenic" treatments for both TSC and non-TSC-related epilepsy. We have previously described a mouse model of TSC that recapitulates many features of human TSC (Tsc1GFAPCKO mice), including severe epilepsy. In the first funding period of this grant, we have described a number of cellular and molecular abnormalities in glia and neurons that contribute to epileptogenesis in these mice, such as astrocyte proliferation, neuronal death, impaired glial buffering of neurotransmitters and potassium ions, and abnormal regulation of specific cell signaling pathways. Most remarkably, we showed that pharmacological inhibition of one of these signaling pathways, the mammalian target of rapamycin (mTOR) pathway, completely prevented the development of epilepsy in Tsc1GFAPCKO mice, representing one of the first demonstrations of a robust anti-epileptogenic effect in any epilepsy model. In this grant renewal application, we propose to extend our previous work, now further characterizing specific TSC-regulated signaling pathways involved in epileptogenesis. Our general hypothesis is that epileptogenesis results primarily from initial abnormalities in specific cell signaling pathways and correction of these signaling abnormalities may prevent epileptogenesis in Tsc1GFAPCKO mice, as well as in other epilepsy models. Findings from this grant should help identify novel mechanisms of epileptogenesis and identify new anti- epileptogenic therapeutic approaches not only for epilepsy in TSC, but potentially for all epilepsy in general.
Epilepsy affects ~1-2% of all people and is associated with increased mortality, as well as significant neurological morbidity, such as memory difficulties, learning disabilities, and mental retardation. The research in this grant aims to determine mechanisms of epileptogenesis in Tuberous Sclerosis Complex, one of the most common genetic causes of epilepsy, as well as in other models of epilepsy, and to develop novel "anti- epileptogenic" therapeutic approaches that do not just suppress seizures but actually correct the underlying brain abnormalities causing epilepsy. Thus, given the high prevalence of epilepsy in the general population, this research has strong relevance to public health and has the potential to have a significant positive impact in improving public health.
|Wong, Michael (2013) A critical review of mTOR inhibitors and epilepsy: from basic science to clinical trials. Expert Rev Neurother 13:657-69|
|Wong, Michael (2013) Mammalian target of rapamycin (mTOR) pathways in neurological diseases. Biomed J 36:40-50|
|Wong, Michael (2013) Mammalian target of rapamycin (mTOR) activation in focal cortical dysplasia and related focal cortical malformations. Exp Neurol 244:22-6|
|Zhang, Bo; McDaniel, Sharon S; Rensing, Nicholas R et al. (2013) Vigabatrin inhibits seizures and mTOR pathway activation in a mouse model of tuberous sclerosis complex. PLoS One 8:e57445|
|Guo, Dongjun; Zeng, Linghui; Brody, David L et al. (2013) Rapamycin attenuates the development of posttraumatic epilepsy in a mouse model of traumatic brain injury. PLoS One 8:e64078|
|Rensing, Nicholas R; Guo, Dongjun; Wong, Michael (2012) Video-EEG monitoring methods for characterizing rodent models of tuberous sclerosis and epilepsy. Methods Mol Biol 821:373-91|
|Guo, Dongjun; Arnspiger, Sarah; Rensing, Nicholas R et al. (2012) Brief seizures cause dendritic injury. Neurobiol Dis 45:348-55|
|Zhang, Bo; Wong, Michael (2012) Pentylenetetrazole-induced seizures cause acute, but not chronic, mTOR pathway activation in rat. Epilepsia 53:506-11|
|Wong, Michael (2011) Epilepsy is both a symptom and a disease: a proposal for a two-tiered classification system. Epilepsia 52:1201-3; discussion 1205-9|
|McDaniel, Sharon S; Wong, Michael (2011) Therapeutic role of mammalian target of rapamycin (mTOR) inhibition in preventing epileptogenesis. Neurosci Lett 497:231-9|
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