Epilepsy is a disease of recurrent seizures that affects up to 1% of the world's population. At present time, we understand very little about how regions of the human brain become epileptic and produce seizures. We also have no medications that cure or prevent epilepsy from forming, a process known as epileptogenesis. Current medications can suppress seizures, but have not been shown to prevent or cure the disease, so that epileptic patients who stop taking their medications continue to have seizures. One approach that can lead to a permanent reduction in seizures is epilepsy surgery to remove focal regions of the brain where seizures start. Long term intracranial recordings that are often performed as part of these surgeries reveal extremely frequent epileptic discharges or 'spikes' often at or near regions of the brain where seizures start, suggesting that these 'interictal' (between seizures) spikes are highly associated with epileptic brain regions. In fact interictal spikes appear before seizures in some animal models of epileptogenesis. However, the exact relationship between interictal spiking and seizures is not known nor is it clear whether treatments that block seizures block spiking or vice versa. Here, we plan to extend our work that has taken an unbiased approach to identify new therapeutic targets for epilepsy based on high throughput genomic studies from precisely localized human neocortical regions from patients who have undergone epilepsy surgery. We will use data acquired from gene expression studies in human epileptic brain to identify genes and molecular pathways associated with interictal spiking and compare these to brain regions that produce seizures, with a specific emphasis on the MAP kinase signaling genes and pathways. The spatial organization of the MAPK signaling intermediates will be mapped to specific laminar and cellular regions as well as to recently discovered `microlesions' in deeper cortical layers that are present in high spiking regions. Finally, both an in vitro model of chronic depolarization together with an in vivo animal model that separates interictal spiking from seizures will be used to test the specific functions o MAP Kinase genes and inhibitors as potential therapeutic targets for both epileptogenesis and established epilepsy.
This project addresses major gaps in our ability to care for patients with epilepsy both by developing a better understanding of epileptic discharge and seizures in the human brain and in a new animal model. The animal model and human tissue studies proposed will identify new targets at test and develop drugs against epilepsy and new ways so that they can rapidly translate back to patients with epilepsy.
| Wu, Helen C; Dachet, Fabien; Ghoddoussi, Farhad et al. (2017) Altered metabolomic-genomic signature: A potential noninvasive biomarker of epilepsy. Epilepsia 58:1626-1636 |
| Jozwiak, Sergiusz; Becker, Albert; Cepeda, Carlos et al. (2017) WONOEP appraisal: Development of epilepsy biomarkers-What we can learn from our patients? Epilepsia 58:951-961 |
