lincRNA-p21调控DNA甲基化介导颞叶内侧癫痫耐药的机制研究

项目名称： lincRNA-p21调控DNA甲基化介导颞叶内侧癫痫耐药的机制研究

项目编号： No.81501127

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 黄程

作者单位： 四川大学

项目金额： 20万元

中文摘要： 颞叶内侧癫痫是临床最常见的耐药性癫痫类型，其耐药机制不清，已成为公认的科学问题和临床难点。研究表明lncRNA表达及功能异常是人类疾病产生的重要原因。lincRNA-p21招募DNA甲基转移酶DNMT1促进DNA甲基化修饰，参与靶基因表观遗传学调控。课题组前期通过海人酸小鼠慢性颞叶癫痫模型，采用表达谱芯片比较药物敏感组与耐药组海马组织lncRNA表达差异，发现lincRNA-p21表达下调与癫痫耐药性具有密切关系，但其具体作用机制不明。我们提出假说，lincRNA-p21下调降低DNMT1对多耐药基因MDR1甲基化修饰，致使MDR1/P-gp过度表达，进而导致癫痫耐药。本项目拟应用慢病毒载体过表达或沉默lincRNA-p21，在动物和细胞模型深入研究lincRNA-p21在癫痫耐药中的作用及分子机制，为以lncRNA为靶点的耐药癫痫治疗提供新的科学依据和理论基础。

中文关键词： 颞叶内侧癫痫；药物难治性癫痫；长非编码RNA；DNA甲基化

英文摘要： The mesial temporal lobe epilepsy is the most common type of refractory epilepsy. The onset mechanism of drug-resistance remains unclear, which has raised great global awareness. The evidence has accumulated that abnormality in the expression and function of lncRNA plays a crucial role in human pathogenesis. Studies have shown that lincRNA-p21 promotes DNA methylation through binding with DNA methyl transferase-1 (DNMT1), engaging in epigenetic regulation of the target genes. We previously established kainic acid (KA) induced chronic epilepsy mouse model, and compared the difference in lncRNA expression in hippocampal region between AEDs-sensitive and AEDs-resistant mice using lncRNA microarray chip. The results indicate that down-regulation of lincRNA-p21 is closely associated with refractory epilepsy. We therefore hypothesize that down-regulation of lincRNA-p21 interferes with MDR-1 gene methylation by DNMT1, leading to elevated expression of MDR1/P-gp, and further engages in mechanism of refractory epilepsy.This project intends to construct lentivirus vectors to upregulate and silence the expression of lincRNA-p21 in animal and cell models, to explore the essential role of lincRNA-p21 in the onset of refractory epilepsy using molecular biological and behavioral measures, and to provide novel evidence and cornerstone for further therapies for refractory epilepsy targeting lncRNA.

英文关键词： Mesial temporal lobe epilepsy;Drug resistant epilepsy;Long non-coding RNA;DNA methylation