基于免疫细胞转录组的多发性硬化症药物重定位。

Immune cells transcriptome-based drug repositioning for multiple sclerosis.

机构信息

Department of Neurology, the Second Affiliated Hospital of Harbin Medical University, Harbin, China.

College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China.

出版信息

Front Immunol. 2022 Oct 20;13:1020721. doi: 10.3389/fimmu.2022.1020721. eCollection 2022.

DOI:10.3389/fimmu.2022.1020721

PMID:36341423

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9630342/

Abstract

OBJECTIVE

Finding target genes and target pathways of existing drugs for drug repositioning in multiple sclerosis (MS) based on transcriptomic changes in MS immune cells.

MATERIALS AND METHODS

Based on transcriptome data from Gene Expression Omnibus (GEO) database, differentially expressed genes (DEGs) in MS patients without treatment were identified by bioinformatics analysis according to the type of immune cells, as well as DEGs in MS patients before and after drug administration. Hub target genes of the drug for MS were analyzed by constructing the protein-protein interaction network, and candidate drugs targeting 2 or more hub target genes were obtained through the connectivity map (CMap) database and Drugbank database. Then, the enriched pathways of MS patients without treatment and the enriched pathways of MS patients before and after drug administration were intersected to obtain the target pathways of the drug for MS, and the candidate drugs targeting 2 or more target pathways were obtained through Kyoto Encyclopedia of Genes and Genomes (KEGG) database.

RESULTS

We obtained 50 hub target genes for CD4 T cells in Fingolimod for MS, 15 hub target genes for Plasmacytoid dendritic cells (pDCs) and 7 hub target genes for Peripheral blood mononuclear cells (PBMC) in interferon-β (IFN-β) for MS. 6 candidate drugs targeting two or more hub targets (Fostamatinib, Copper, Artenimol, Phenethyl isothiocyanate, Aspirin and Zinc) were obtained. In addition, we obtained 4 target pathways for CD19 B cells and 15 target pathways for CD4 T cells in Fingolimod for MS, 7 target pathways for pDCs and 6 target pathways for PBMC in IFN-β for MS, most of which belong to the immune system and viral infectious disease pathways. We obtained 69 candidate drugs targeting two target pathways.

CONCLUSION

We found that applying candidate drugs that target both the "PI3K-Akt signaling pathway" and "Chemokine signaling pathway" (e.g., Nemiralisib and Umbralisib) or applying tyrosine kinase inhibitors (e.g., Fostamatinib) may be potential therapies for the treatment of MS.

摘要

目的

基于多发性硬化症（MS）免疫细胞的转录组变化，寻找现有药物在 MS 中的再定位的靶基因和靶途径。

材料与方法

基于基因表达综合数据库（GEO）数据库中的转录组数据，根据免疫细胞的类型，通过生物信息学分析确定未经治疗的 MS 患者的差异表达基因（DEGs），以及药物治疗前后 MS 患者的 DEGs。通过构建蛋白质-蛋白质相互作用网络分析药物的枢纽靶基因，并通过连接图谱（CMap）数据库和 Drugbank 数据库获得针对 2 个或更多枢纽靶基因的候选药物。然后，将未经治疗的 MS 患者的富集途径与药物治疗前后 MS 患者的富集途径进行交集，获得药物针对 MS 的靶途径，并通过京都基因与基因组百科全书（KEGG）数据库获得针对 2 个或更多靶途径的候选药物。

结果

我们获得了芬戈莫德治疗 MS 时 CD4 T 细胞的 50 个枢纽靶基因、干扰素-β（IFN-β）治疗 MS 时浆细胞样树突状细胞（pDC）的 15 个枢纽靶基因和外周血单核细胞（PBMC）的 7 个枢纽靶基因。获得了针对 2 个或更多枢纽靶基因的 6 种候选药物（福他替尼、铜、青蒿素、苯乙基异硫氰酸酯、阿司匹林和锌）。此外，我们获得了芬戈莫德治疗 MS 时 CD19 B 细胞的 4 个靶途径和 CD4 T 细胞的 15 个靶途径、IFN-β 治疗 MS 时 pDC 的 7 个靶途径和 PBMC 的 6 个靶途径，其中大多数属于免疫系统和病毒传染病途径。我们获得了针对 2 个靶途径的 69 种候选药物。