Regulation of epileptogenesis by the transcriptional repressor, REST

描述（由申请人提供）：人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，最终导致自发性癫痫发作的出现，即，癫痫这个过程的早期事件似乎是由转录抑制因子REST参与的。我们的假设，初步证据支持，是由癫痫持续状态的REST诱导调节癫痫发生的许多方面，包括神经变性，认知障碍，神经发生和自发性癫痫发作的发展。具体目的是1）鉴定SE后由REST直接调控的齿状颗粒细胞表达的主要基因组，并比较HDAC 2和G9 a的条件突变以及I类HDAC、G9 a组蛋白甲基转移酶和LSD 1/SMCX组蛋白去甲基化酶的抑制对其SE诱导的REST介导的转录谱的影响。2)为了确定是否有条件突变的REST在前脑神经元的一个子集钝化神经变性，认知缺陷，和神经发生后SE。3)比较REST的条件性突变和（取决于目标1的结果）HDAC 2、G9 a和LSD 1的条件性突变或SE后抑制减少SE后癫痫发展的能力。将比较毛果芸香碱和红藻氨酸盐SE模型，以尽量减少模型特定的结论。遗传学和药理学方法将用于追求这些目标。策略将涉及REST，HDAC 2和G9 a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.