利用生物信息学分析酪氨酸激酶抑制剂治疗斑秃的效应机制

Mechanism of Janus Kinase Inhibitors in the Treatment of Alopecia Areata Using Bioinformatics Analysis

目的利用生物信息学分析鲁索利替尼、托法替尼对斑秃(AA)小鼠皮损皮肤组织的基因表达的影响,为酪氨酸激酶(JAK)抑制剂治疗AA的临床应用及其机制研究提供参考。方法在PubMed GEO DataSets中下载基因芯片数据GSE45514(ID:5273),采用R软件、Cytoscape软件、STRING 11.0、基因信息分析平台(GCBI)基因雷达分析等分析软件,筛选鲁索利替尼、托法替尼干预AA小鼠12周后皮损皮肤组织较干预前共同的差异表达基因,探讨差异基因的蛋白-蛋白相互作用、涉及的生物学功能和信号通路以及关键基因等。结果AA小鼠经鲁索利替尼、托法替尼干预12周后皮损皮肤组织中有18个共同的显著差异表达基因,主要参与免疫系统过程调节、免疫应答、趋化因子介导信号通路等生物过程。CCL5为蛋白网络核心节点,可激活下游基因CCR1~10、CXCR1~6、XCR1、CX3CR1,与炎性反应、自身免疫性疾病等相关,经2种药物治疗后皮损皮肤组织中表达明显降低。结论通过生物信息学分析发现JAK抑制剂可使AA小鼠皮损皮肤组织中基因表达谱发生改变,其可能通过下调CCL5基因表达促进AA的好转。

Objective In order to analyze the effects of Ruxolitinib and Tofacitinib on the gene expression of lesional skin tissue in alopecia areata(AA)mice using bioinformatics analysis,and to provide references for the clinical application and mechanism of janus kinase inhibitors in the treatment of AA.Methods The GeneChip Data GSE45514(ID:5273)in PubMed GEO DataSets was downloaded,and the analytical software such as R software,Cytoscape software,STRING 11.0,GCBI gene radar analysis,etc.were used to screen the common differentially expressed genes in lesional skin tissue of AA mice after treated by Ruxolitinib and Tofacitinib for twelve weeks comparing with before intervention,explore protein-protein interactions,biological functions,signaling pathways and the key gene of the common differential genes.Results There were eighteen common differentially expressed genes in lesional skin tissue of AA mice after treated by Ruxolitinib and Tofacitinib for twelve weeks comparing with before intervention,and they were mainly involved in biological processes such as immune system process regulation,immune response,chemokine-mediated signaling pathways,etc.CCL5 was the core node of the protein network,and it could activate the downstream genes CCR1~10,CXCR1~6,XCR1,CX3CR1,and was related to inflammation,autoimmune diseases,etc.Its expression in lesional skin tissue was significantly reduced after treatment with the two drugs.Conclusion Janus kinase inhibitors can alter the gene expression profile in skin lesions of AA mice using bioinformatics analysis,which may promote the improvement of AA by down-regulating CCL5 gene expression.