肝脏X受体激动剂相关阿尔茨海默病的关键基因和信号通路研究

The study on key genes and signaling pathways of liver X receptor agonists associated Alzheimer disease

目的探索肝脏X受体(LXR)激动剂相关阿尔茨海默病(AD)的分子机制,为AD治疗的研究提供指导。方法自GEO数据库中下载数据集GSE31624的原始基因芯片数据,按照AD动物模型(Tg2576小鼠)的处理方法(注射和不注射LXR激动剂苯甲磺酰胺),将所有样本的基因芯片数据分为LXR组和AD组两组,每组11只。对原始数据进行标准化,用R语言中的Limma包通过贝叶斯检验分析得到差异表达基因(DEGs)。之后利用DAVID数据库对DEGs进行基因本体论(GO)分析,通过KEGG数据库对DEGs进行通路富集分析,并利用STRING数据库构建蛋白质-蛋白质相互作用(PPI)网络,通过Cytoscape软件进行可视化处理,利用CytoHubba插件分析得到互作强度最高的基因(Hub基因)。结果总共得到665个DEGs,其中上调基因284个,下调基因381个。GO分析结果表明,DEGs主要位于乙酰胆碱门控通道复合物,其功能主要集中于突触传递、脂蛋白运输、细胞内信号转导的正调节和神经肌肉突触传递等过程。KEGG分析结果显示Ras信号通路、5-腺嘌呤核苷酸(AMP)依赖的蛋白激酶(AMPK)信号通路、Janus激酶(Jak)-信号转导与转录激活剂(STAT)信号通路、磷脂酰肌醇-4,5-双磷酸3-激酶(PI3K)-胸腺嘧啶核苷激酶(AKT)信号通路、丝裂原活化蛋白激酶(MAPK)信号通路等信号通路在LXR激动剂治疗AD的机制中发挥着重要的作用。通过PPI网络分析共得到Cftr、Lrp2、Rnf144b、Tfrc、Uba52、Slc18a3、Aak1、Dvl2、Dab2、Arpc5、Ube4a、Trim71、Asb1、Ube2v2、Rnf220和Asb17等16个Hub基因。结论通过分析LXR激动剂治疗AD相关的基因芯片数据,发现了可能发挥重要作用的Cftr、Lrp2、Rnf144b、Tfrc、Uba52、Slc18a3、Aak1、Dvl2、Dab2、Arpc5、Ube4a、Trim71、Asb1、Ube2v2、Rnf220和Asb17等16个关键基因,以及Ras信号通路、AMPK信号通路和Jak-STAT信号通路等8个关键的信号通路,它们可能是LXR激动剂治疗AD的作用靶点。

Objective To explore the molecular mechanism of LXR on Alzheimer disease(AD)and provide guidance for the research on the treatment of AD.Methods We downloaded the original gene chip data of dataset GSE31624 from the GEO database.According to the treatment method to the AD animal model(Tg2576 mouse)(injection of LXR agonist benzenesulfonamideand non-injection of LXR agonistbenzenesulfonamide),the gene chip data of all the samples were divided into an LXR group and an AD group with 11 mice in each group.Then,the original data were standardized,and the differential expression genes(DEGs)were obtained by Bayesian test analysis with Limma packets in R language.Then,the gene ontology(GO)analysis of DEGs was carried out by DAVID database,and the pathway enrichment analysis of DEGs was carried out by KEGG database.Finally,the protein-protein interaction(PPI)network was constructed by using STRING database,visualized by Cytoscape software,and the genes with the highest interaction intensity(Hub gene)were obtained by using cytoHubba plug-in.Results A total of 665 DEGs were obtained,including 284 up-regulated genes and 381 down-regulated genes.GO analysis results showed that DEGs were mainly located in the acetylcholine gating channel complex,and their functions mainly focused on synaptic transmission,lipoprotein transportation,processes such as positive regulation of intracellular signal transduction and neuromuscular synaptic transmission.KEGG analysis results showed that Ras signal pathway,AMPK signal pathway,Jak-STAT signal pathway,PI3K-Akt signal pathway and MAPK signal pathway played an important role after LXR agonist administration.A total of 16 Hub genes including Cftr,Lrp2,Rnf144b,Tfrc,Uba52,Slc18a3,Aak1,Dvl2,Dab2,Arpc5,Ube4a,Trim71,Asb1,Ube2v2,Rnf220 and Asb17 were obtained through protein interaction network analysis.Conclusions By analyzing the gene chip data of LXR agonist in the treatment of AD,16 key genes such as Cftr,Lrp2,Rnf144b,Tfrc,Uba52,Slc18a3,Aak1,Dvl2,Dab2,Arpc5,Ube4a,Trim71,Asb1,Ube2v2,Rnf220 and Asb17 were found,as well as 8 signaling pathways such as Ras signaling pathway,AMPK signaling pathway and Jak-STAT signaling pathway,may be direct or indirect therapeutic targets for LXR agonists.All of these may be the target of LXR agonist in the treatment of AD.