重型再生障碍性贫血发病相关T淋巴细胞基因表达谱的生物信息学分析及作为药物筛选新方法的探索  

Gene Expression Profile Analysis of T Lymphocytes Involved in Pathogenesis of Severe Aplastic Anemia by Using Bioinformatics Method as A Novel Way of Drug Screening

作　　者：卢学春[1] 迟小华[2] 杨波[1] 朱宏丽[1] 刘丽宏[2] 张峰[3] 严江伟[3] 

机构地区：[1]解放军总医院南楼血液科,北京100853 [2]解放军第二炮兵总医院药剂科,北京100800 [3]中国科学院北京基因组研究所,北京100029

出　　处：《中国实验血液学杂志》2010年第2期416-420,共5页Journal of Experimental Hematology

基　　金：国家自然科学基金资助项目(编号30772597和30873086);科技部重大新药创制课题资助项目(编号2008JXJ09001-019)

摘　　要：本研究初步探索重型再生障碍性贫血(severe aplastic anemia,SAA)发病相关的T淋巴细胞基因表达谱特征,并根据药物与疾病基因表达谱相似性对比的原理,探索SAA治疗药物新的筛选方法。以SAA和T淋巴细胞为关键词,在人类基因表达数据库和基因芯片数据库中检索与SAA发病相关的基因表达数据库,并对此基因表达数据库进行显著性检验后筛选与SAA发病相关的基因表达谱,并进行聚类分析。然后,在3 000种药物基因表达谱数据库中筛选与SAA发病相关基因表达谱特征相反者。结果表明,在上述数据库中检索到1个满足条件的相关基因表达数据库GSE3807。与SAA发病相关的T淋巴细胞基因一共有515个(表达水平变化超过2倍),其中上调者202个,下调者313个。聚类分析发现,这些基因分别属于核酸代谢、泛素依赖的蛋白降解通路、免疫球蛋白/主要组织相容性复合体、高尔基体蛋白运输以及蛋白质磷酸化等通路。SAA发病相关基因与药物基因表达谱相似性分析发现,羟基喜树碱、盐酸二甲双胍可能具有治疗SAA的作用。结论:采用生物信息学方法,比较疾病发病相关基因表达谱与药物基因表达谱的相似性,有可能成为SAA治疗药物筛选的新方法。This study was aimed to explore the gene expression profile characteristics of T lymphocytes involved in pathogenesis of severe aplastic anemia （ SAA ） and to predict putative curative drugs for SAA by using biological principle of similarity contrast of gene expression profiles between drugs and diseases. SAA and T lymphocyte were used as key words to search gene expression datasets related to pathogenesis of SAA in public Gene Expression Omnibus （GEO） of NCBI. After significance test, gene expression profilings involved in pathogenesis of SAA were screened and applied to cluster analysis. And then SAA-related gene expression profiles were thrown into pharmacological gene expression datasets of 3000 candidate drugs for similarity analysis and significantly negative correlation was used as a screening criterion for selecting putative curative drugs of SAA. The results showed that only one gene expression dataset was found out, i.e. GSE3807. Computational bioanalysis identified a total of 515 candidate genes of T lymphocyte involved in pathogenesis of SAA, whose expression level exceeded more than 2-fold. Among them, 202 genes were upregulated and 313 genes were downregulated. Cluster analysis showed that those genes belonged to different pathways, including nucleic acid metabolic process, ubiquitin-dependent protein catabolic process, Golgi apparatus protein transport, protein phosphorylation and immunoglubin/major histocompatability complex. Similarity analysis of gene expression profiles of SAA and drugs showed that hydroxycamptothecin and metformin might have a potential therapeutic efficacy on SAA. It is concluded that by means of novel bioinforrnatics method, gene expression profiling combined with similarity analysis between disease-related gene expression and pharmacological gene expression profiles may be a novel way of drug screening for SAA.

关 键 词：重型再生障碍性贫血 生物信息学 T淋巴细胞 羟喜树碱 盐酸二甲双胍 

分 类 号：R556.5[医药卫生—血液循环系统疾病]