基因表达标签相似性比较的抗辐射药物重定位研究

Radioprotectors Drug Repurposing Discovery Based on Comparing Similarity of Gene Expression Signature

目的:探讨基于表达谱标签相似性比较的途径从上市药物中筛选发现抗辐射损伤治疗药物。方法:从GEO数据库获得辐射损伤基因表达谱数据集GSE26835,利用RMA和SAM软件对表达谱芯片数据进行差异表达基因分析,获得辐射损伤基因标签,最后通过connectivity map数据库进行检索,并对检索结果进行实验验证。结果:获得的辐射基因标签包含上调基因134个,下调基因73个,这些基因生理功能主要集中于DNA损伤应激,DNA修复,细胞周期阻滞等;通过Cmap分析,筛选到阿米洛利,潘必啶等候选药物,其中阿米洛利负相关指数最高,进一步实验验证证明阿米洛利在体外和体内实验中都具有较好的抗辐射活性。结论:基于基因表达谱的药物重定位可从上市药物中筛选到有效的抗辐射药物为发现老药的新用途提供了新的途径。

Objective： To investigate new radio-protectors using network pharmacology based on genome-wide expression profiling technology. Methods： The radiation damage gene expression data GSE26835 was obtained from GEO database, and radiation damage gene signature was generated by using RMA and SAM software. The radiation gene signature was used to retrieve connectivity map database, and the permuted results were experimentally validated. Results： The radiation gene signature consisted of 134 up-regulated genes and 73 down-regulated genes, and the biological functions of these genes were mainly about DNA damage response, DNA repair and cell cycle arrest. The Cmap permuted result showed some candidate drugs, including amiloride, pempidine and so on. Amiloride had the strongest negative score among them. Further experiment confirmed that amiloride had radioprotection effect both in vitro and in vivo. Conclusion： Drug repurposing based on genome-wide expression profiling technology provides a new strategy in drug discovery, and becomes an important part of network pharmacology.