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神经元活性调控的盐诱导激酶1在癫痫发病过程中的作用及分子细胞机制研究

批准号81571268 学科分类神经电活动异常与发作性疾病 ( H0913 )
项目负责人谭国鹤 负责人职称教授 依托单位广西医科大学
资助金额57.00
万元
项目类别面上项目 研究期限2016 年 01 月 01 日 至
2019 年 12 月 31 日
中文主题词癫痫病;癫痫发生;盐诱导激酶1;癫痫发作;电刺激点燃模型
英文主题词Epilepsy;Epileptogenesis;Sik1;Seizure activity;Kindling model

摘要

中文摘要 癫痫是常见的破坏性脑部疾病,但其发病机制迄今仍不够清楚。既往研究表明,活性依赖的基因表达在癫痫发生过程中发挥着关键作用。我们根据当前进展推测盐诱导激酶Sik1可能与颞叶癫痫有关,预实验发现Sik1可受癫痫发作诱导,基因敲除后Kindling进程加快。据此重要线索,我们拟使用经典的颞叶癫痫动物模型,采用分子、免疫和细胞学的方法来系统观察Sik1在癫痫脑内的表达规律、活性状况和分布变化,综合使用基因敲除小鼠、病毒感染、药理学操作等研究手段来探索Sik1在颞叶癫痫发生过程中的具体作用,进一步通过条件性基因敲除、电生理记录等策略来探讨Sik1功能的细胞环路机制,结合基因芯片、蛋白质谱和分子克隆等技术来解析Sik1相关的表观遗传修饰、靶基因转录调节改变对癫痫的调控,深入阐明相应的分子机制。本项目首次研究Sik1在癫痫脑内的功能,将促进我们对颞叶癫痫发病机制的新认识,为寻找癫痫防治新靶点提供科学依据。
英文摘要 Epilepsy is a very common devastating brain disorder with about 1% prevalence worldwide. However, the molecular and cellular mechanisms underlying pathogenesis of limbic epilepsy remain largely obscure. Converging evidences from neurobiological studies have implicated the important role of activity-dependent gene expression during the process of epileptogenesis. Here we propose activity-regulated salt-inducible kinase 1 (Sik1) may be involved in epilepsy, based on recent findings. Our preliminary data showed that Sik1 was up-regulated by limbic seizures and deletion of Sik1 gene markedly accelerated kindling process. To further clarify the action of Sik1 in epileptic brain, we will use classic animal models of limbic epilepsy to perform a series of experiments by molecular, cellular, and immunohistological tools, and systematically explore the expression pattern, kinase activity, subcellular translocation of Sik1 in mouse brain. Then we will combine multiple research strategies, such as gene knocking-out, virus infection, and pharmacological manipulation, and so on, to determine the possible role of Sik1 in limbic epileptogenesis. Furthermore, Cre/Loxp-mediated conditional knockout, electrophysiological recording will be used to dissect out the cellular mechanisms of Sik1 function. In more detail, we will analyze the gene transcription regulation changed by Sik1, screen out key target genes, and ultimately identify the underlying molecular mechanisms by performing experiments about gene chips, mass spectrum, and molecular cloning,et al. This work will directly provide the first in vivo evidence for the biological function of Sik1 in epileptic brain and give us new insights into our understanding on the mechanisms of epilepsy. Importantly, the proposed findings will greatly help us to develop novel therapeutic targets against limbic epilepsy.
结题摘要

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