Status epilepticus (SE) in man and rodents can produce cognitive deficits and trigger a series of molecular and cellular events that eventually culminate in the appearance of spontaneous seizures, i.e., epilepsy. An early event in this process appears to be engaged by the transcriptional repressor, REST. Our hypothesis, supported by preliminary evidence, is that REST induction by status epilepticus regulates many aspects of epileptogenesis, including neurodegeneration, cognitive impairments, neurogenesis and the development of spontaneous seizures.
Specific aims are 1) To identify the principal set of genes expressed by dentate granule cells that are directly regulated by REST after SE, and to compare the effect of conditional mutation of HDAC2 and G9a, and inhibition of class I HDACs, G9a histone methyltransferase and LSD1/SMCX histone demethylase, on their SE-induced, REST-mediated transcriptional profile. 2) To determine whether conditional mutation of REST in a subset of forebrain neurons blunts the neurodegeneration, cognitive deficits, and neurogenesis that occur after SE. 3) To compare the ability of conditional mutation of REST and (depending on the outcome of aim 1) conditional mutation or post-SE inhibition of HDAC2, G9a, and LSD1, to reduce the development of epilepsy after SE. A comparison of the pilocarpine and kainate SE models will be done to minimize model-specific conclusions. Both genetic and pharmacologic approaches will be used to pursue these aims. Strategies will involve conditional mutations of REST, HDAC2 and G9a, together with selective inhibitors of the REST epigenetic effector enzymes.
Epilepsy acquired after head injury, status epilepticus, or other triggers can be a devastating neurologic disorder. Currently no therapies exist to prevent the development of epilepsy in someone at risk. Our work aims to examine carefully the potential involvement of one of the most likely mediators of this process. If successful our work will identify novel targets for new drug development.
| Dingledine, Ray; Hassel, Bjørnar (2016) A New Approach for Epilepsy. Cerebrum 2016: |
| Cho, Kyung-Ok; Lybrand, Zane R; Ito, Naoki et al. (2015) Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline. Nat Commun 6:6606 |
| Varvel, Nicholas H; Jiang, Jianxiong; Dingledine, Raymond (2015) Candidate drug targets for prevention or modification of epilepsy. Annu Rev Pharmacol Toxicol 55:229-47 |
| Vezzani, Annamaria; Dingledine, Raymond; Rossetti, Andrea O (2015) Immunity and inflammation in status epilepticus and its sequelae: possibilities for therapeutic application. Expert Rev Neurother 15:1081-92 |
| Jiang, Yindi; Hsieh, Jenny (2014) HDAC3 controls gap 2/mitosis progression in adult neural stem/progenitor cells by regulating CDK1 levels. Proc Natl Acad Sci U S A 111:13541-6 |
| Dingledine, Ray; Varvel, Nicholas H; Dudek, F Edward (2014) When and how do seizures kill neurons, and is cell death relevant to epileptogenesis? Adv Exp Med Biol 813:109-22 |
| Hsieh, Jenny (2012) Orchestrating transcriptional control of adult neurogenesis. Genes Dev 26:1010-21 |
| Roopra, Avtar; Dingledine, Raymond; Hsieh, Jenny (2012) Epigenetics and epilepsy. Epilepsia 53 Suppl 9:2-10 |
| Gao, Zhengliang; Ding, Peiguo; Hsieh, Jenny (2012) Profiling of REST-Dependent microRNAs Reveals Dynamic Modes of Expression. Front Neurosci 6:67 |
