Regulation of epileptogenesis by the transcriptional repressor, REST

描述(申请人提供)：人类和啮齿动物的癫痫持续状态(SE)可产生认知缺陷，并触发一系列分子和细胞事件，最终导致自发癫痫的出现，即癫痫。这个过程中的一个早期事件似乎是由转录抑制因子REST参与的。我们的假说得到了初步证据的支持，即癫痫持续状态的休息诱导调节癫痫发生的许多方面，包括神经退行性变、认知障碍、神经发生和自发性癫痫的发展。具体目标是：1)确定SE后受REST直接调控的齿状颗粒细胞表达的主要基因，比较HDAC2和G9a的条件性突变以及抑制I类HDACs、G9a组蛋白甲基转移酶和LSD1/SMCX组蛋白去甲基酶对SE诱导的REST介导的转录谱的影响。2)确定前脑神经元子集REST的条件性突变是否能钝化SE后发生的神经变性、认知缺陷和神经再生。3)比较静息状态下HDAC2、G9a和LSD1的条件突变和(取决于目标1的结果)条件突变或SE后抑制HDAC2、G9a和LSD1的能力，以减少SE后癫痫的发生。将对匹罗卡品和海人藻酸盐SE模型进行比较，以最小化特定于模型的结论。遗传和药理学方法都将用于实现这些目标。策略将涉及REST、HDAC2和G9a的条件突变，以及REST表观遗传效应酶的选择性抑制剂。

DESCRIPTION (provided by applicant): 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.