快速老化痴呆小鼠海马组织差异表达基因模式分析及治疗药物预测

Analysis of differential expression gene pattern and potential drugs in hippocampus of SAMP8 mice

目的采用网络集成式细胞内特征的公共数据库(LINCS)分析快速老化痴呆小鼠海马组织差异表达基因的表达模式,并预测其潜在的治疗药物。方法选择2月龄、8月龄SAMP8小鼠各20只,2月龄、8月龄SAMR1小鼠各20只,处死后取海马组织,制作基因芯片。采用LINCS数据库GEO2Enrichr分析SAMP8、SAMR1小鼠海马组织快速老化基因表达模式,进行差异表达快速老化基因的GO富集分析,分析其KEGG代谢途径。采用CREEDS网络在线分析工具定性分析快速老化基因的转录模式,采用小分子药物模块定性分析预测老年性痴呆的治疗药物。结果快速老化SAMP8小鼠海马组织基因表达以上调为主,正常老化SAMR1小鼠海马组织基因表达以下调为主。GO富集分析结果显示,SAMP8小鼠海马组织表达上调基因主要定位于细胞核糖体、线粒体,主要生物学过程是细胞中蛋白质合成分选、定位以及病毒核酸合成,主要分子功能是NADH还原酶活性; KEGG代谢途径分析结果显示,SAMP8小鼠海马组织表达上调基因参与的代谢网络途径主要是线粒体氧化磷酸化途径、3种神经退行性疾病代谢途径(阿尔茨海默病、帕金森病和亨廷顿病)、核糖体蛋白质合成途径及非酒精性脂肪肝、大肠杆菌感染代谢网络途径;基因转录模式定性分析结果显示,SAMP8小鼠海马组织快速老化基因表达模式与单基因模块Psap(典型的神经元保护模式)匹配度最高,SAMR1小鼠基因表达模式与单基因模块Pink1匹配度最高。小分子药物模块定性分析结果显示,匹配度最高的小分子药物是维生素PP。结论 SAMP8小鼠海马组织基因表达以神经元保护为主要特征,是一种特殊的细胞线粒体修复模式,其线粒体相关基因表达显著上调。维生素PP可能是老年性痴呆的有效治疗药物。

Objective To analyze differential expression gene pattern in the hippocampus of senescence-accelerated mouse-prone 8(SAMP8)mice and to predict the effective drugs by using network integrated public database of intracellular characteristics(LINCS).Methods Twenty two-month and 20 eight-month SAMP8 mice were selected as the accelerated-aging models of dementia,and SAMR1 mice at the same age were used as the controls of normal aging.Total RNA from hippocampus was used to Gene chip hybridization in mice.The LINCS database GEO2Enrichr was used to analyze the expression patterns of rapid aging genes in hippocampus of SAMP8 and SAMR1 mice,and the GO enrichment analysis of differentially expressed rapid aging genes was carried out to analyze the KEGG metabolic pathway.We used the CREEDS online analysis tool to qualitatively analyze the transcription pattern of rapid aging genes,and used small molecule drug modules to qualitatively analyze and predict the therapeutic drugs for senile dementia.Results Gene transcription pattern was characterized by up-regulation of gene expression in the SAMP8 mice of rapid aging,and gene transcription pattern was characterized by down-regulation of gene expression in SAMR1 mice of normal aging.GO enrichment analysis results showed that the up-regulated genes in SAMP8 mice were mainly located in the ribosome and mitochondria of cells,the main biological processes were the mechanism of protein synthesis,sorting,localization and viral nucleic acid synthesis in cells,and the main molecular function was NADH reductase activity.KEGG metabolic pathway analysis showed that the main pathways of metabolic network involved in the up-regulation of gene expression in hippocampus of SAMP8 mice were oxidative phosphorylation of mitochondria,3 neurodegenerative pathways(Alzheimer′s disease,Parkinson′s disease and Huntington′s disease)and ribosomal protein synthesis pathways,non-alcoholic fatty liver and Escherichia coli infection pathway.Qualitative analysis of gene transcription patterns showed that SAMP8 mice matched the single gene module Psap best and SAMR1 mice matched the single gene module Pink1 best.Qualitative analysis of small molecule drug modules showed that the most well-matched small molecule drug was vitamin PP.Conclusion Neuron protection is the main feature of gene expression in aged SAMP8 mice which is a special mitochondrial stress response mode(mtUPR).The expression of mitochondria-related genes was significantly up-regulated.Vitamin PP may be an effective drug for Alzheimer′s disease.