let-7g介导的ceRNA调控网络对奥氮平/氯氮平相关代谢综合征的作用机制研究

项目名称： let-7g介导的ceRNA调控网络对奥氮平/氯氮平相关代谢综合征的作用机制研究

项目编号： No.81501154

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： 陈剑华

作者单位： 上海市精神卫生中心

项目金额： 21万元

中文摘要： 代谢综合征是非典型抗精神病药物常见不良反应，严重影响治疗的依从性。其中奥氮平与氯氮平较其它抗精神病药物更易产生代谢综合征，但其内在机制尚不明确。let-7g是连接炎症反应、糖脂代谢的重要中介。课题组前期研究发现药源性代谢综合征的患者let-7g表达下调，通过生物信息学分析提示let-7g参与体内多条代谢相关信号通路，在其介导的竞争性内源RNA（ceRNA）调控网络中，lncRNA（HMGA2、TGFBR3、H19等）可作为ceRNA参与调控糖脂代谢。本项目拟进一步采用RNA-Seq补充转录组学数据，分析lncRNA-miRNA-mRNA相互作用通路。并针对let-7g及其介导的ceRNA构建RNAi及过表达载体，观察用药前后小鼠3T3-L1前脂肪细胞表型变化、检测此通路上下游基因的mRNA及蛋白水平变化情况，验证ceRNA调控网络及其功能，为探索药物相关代谢综合征的机制提供新的依据。

中文关键词： 精神分裂症；非典型抗精神病药；代谢综合征；长链非编码RNA；竞争性内源RNA

英文摘要： Metabolic syndrome is the common adverse reaction triggered by atypical antipsychotics, which will seriously influence the treatment adherence. Compared with other antipsychotics, olanzapine and clozapine are more vulnerable to metabolic syndrome, while the mechanics underlying this adverse reaction remain unclear. As a connection of inflammation and carbohydrate metabolism, let-7g was an important intermediary in glucose and lipid metabolism disorders. Previous research of our institute found down-regulation of let-7g among patients taking atypical antipsychotic with metabolic syndrome. Bioinformatics analysis demonstrated that lncRNA (HMGA2, TGFBR3, H19) could serve as competitive RNA(ceRNA) in the metabolism of glucose and lipid within the internally competitive RNA(ceRNA) regulatory network meditated by let-7g. The project aims to further complement transcriptomics data via RNA-Seq to analyze miRNA-mRNA-lncRNA interaction pathways. As for let-7g and let-7g mediated ceRNA , we will conduct overexpression or RNAi vectors in vitro murine 3T3-L1 preadipocytes model to detect the relative alteration of cell phenotype, mRNA and the protein of upstream and downstream. We would also verify ceRNA and the regulatory networks, providing novel evidence for the mechanism of atypical antipsychotic in drug related metabolic syndrome.

英文关键词： schizophrenia;atypical antipsychotics;metabolic syndrome;lncRNA;ceRNA