基于疾病基因表达谱的糖尿病肾病治疗药物预测

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摘要目的探讨基因表达谱在筛选糖尿病肾病有效治疗药物中的应用效果。方法在GEO数据库中搜索与糖尿病肾病相关的基因芯片，利用d-chip软件进行差异基因的表达分析，采用基因集富集的方法（GSEA）进行相关信号通路的富集分析，再利用Cmap筛选治疗糖尿病肾病的候选药物，并通过动物实验进行药效学评估。结果通过对GSE31022芯片中的合格样本进行差异基因的有效分析，在获得的540个差异表达基因中，上调基因150个，下调基因390个；通过GSEA分析主要富集到NF-κB信号通路与糖尿病肾病最为密切（P ＜ 0.05），并且筛选出甲砜霉素可能对糖尿病肾病有治疗作用（score=1），动物实验结果显示，与模型组比较，甲砜霉素组的肾小球硬化及系膜扩张明显改善，基本达到正常组水平，差异有统计学意义（P ＜ 0.05）。此外，甲砜霉素组的尿蛋白和CD68、转化生长因子β、纤溶酶原激活物抑制物1及白介素6的mRNA水平低于模型组（P ＜ 0.05）。结论基于糖尿病肾病相关基因表达谱作为疾病有效治疗药物的预测手段，为疾病的治疗药物发现提供了新思路。

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	史晓贤1 李高文2

关键词 ：基因芯片, 糖尿病肾病, 甲砜霉素, 基因表达谱, 富集分析

Abstract：Objective To explore the application effects of gene expression profiling in screening the effective therapeutic drugs for diabetic nephropathy. Methods The gene chips related to diabetic nephropathy in GEO databases were searched and the differential gene expression was analyzed by d-chip software. Enrichment analysis of the relevant signaling pathways was carried out by GSEA, Cmap was then used for the screening of candidate drugs of diabetic nephropathy and pharmacodynamic validation was evaluated in animal experiments. Results Through the analysis of differential genes in qualified samples from the GSE31022 chip, a total of 540 genes were obtained, of which, 150 genes were up-regulated and 390 genes were down-regulated. The main enrichment to NF-κB signaling pathway by GSEA was most closely related to diabetic nephropathy (P ＜ 0.05), and screening for Thiamphenicol may have a therapeutic effect on diabetic nephropathy (score=1). The results of animal experiments showed that compared with model group, the mesangial expansion of the diabetic nephropathy mice treated by Thiamphenicol was significantly improved and almost reached the normal level (P ＜ 0.05). In addition, the levels of urine protein and the mRNA levels of CD68, transforming growth factor β, plasminogen activator inhibitor 1 and interleukin 6 in the Thiamphenicol group were significantly lower than those in model group (P ＜ 0.05). Conclusion As an effective means of predicting effective therapeutic drugs for diabetic nephropathy, the gene expression profiling based on diabetic nephropathy provides a new idea for the discovery of therapeutic drugs for the disease.

Key words： Gene chips Diabetic nephroathy Thiamphenicol Gene expression profiling Enrichment analysis

基金资助:浙江省宁波市自然科学基金项目（2017A610213）。

通讯作者: 李高文（1985.9-），男，硕士；研究方向：计算机药物辅助设计。

引用本文:

史晓贤1 李高文2. 基于疾病基因表达谱的糖尿病肾病治疗药物预测[J]. 中国医药导报, 2018, 15(22): 18-21,26.
SHI Xiaoxian1 LI Gaowen2. Prediction of therapeutic drugs for diabetic nephropathy based on disease gene expression profiling. 中国医药导报, 2018, 15(22): 18-21,26.

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http://www.yiyaodaobao.com.cn/CN/ 或 http://www.yiyaodaobao.com.cn/CN/Y2018/V15/I22/18

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