Regulation of epileptogenesis by the transcriptional repressor, REST

描述（由申请人提供）：人类和啮齿动物的癫痫持续状态（SE）可产生认知缺陷，并引发一系列分子和细胞事件，最终导致自发性癫痫发作，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。我们的假设得到了初步证据的支持，即癫痫持续状态诱导的REST调节了癫痫发生的许多方面，包括神经变性、认知障碍、神经发生和自发癫痫发作的发展。具体目的是：1)鉴定SE后齿状颗粒细胞直接受REST调控的主要表达基因，比较HDAC2和G9a条件突变以及抑制I类hdac、G9a组蛋白甲基转移酶和LSD1/SMCX组蛋白去甲基化酶对SE诱导的REST介导的转录谱的影响。2)确定部分前脑神经元REST的条件突变是否会减弱SE后发生的神经变性、认知缺陷和神经发生。3)比较REST条件突变和（取决于目的1的结果）HDAC2、G9a和LSD1条件突变或SE后抑制对SE后癫痫发展的影响。将对匹罗卡品和海因酸盐SE模型进行比较，以尽量减少模型特异性结论。遗传学和药理学方法都将用于实现这些目标。策略包括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.