球形细胞脑白质营养不良的关键免疫相关基因和药物候选物分析

doi:10.16352/j.issn.1001-6325.2025.06.0727

基础医学与临床 ›› 2025, Vol. 45 ›› Issue (6): 727-734.doi: 10.16352/j.issn.1001-6325.2025.06.0727

球形细胞脑白质营养不良的关键免疫相关基因和药物候选物分析

罗贵元¹, 李扬², 张业^1*, 吕亚丰^2*

1.中国医学科学院基础医学研究所北京协和医学院基础学院生物化学与分子生物学系,北京 100005;
2.三峡大学基础医学院肿瘤微环境与免疫治疗湖北省重点实验室,湖北宜昌 443000

收稿日期:2025-02-20 修回日期:2025-03-21 出版日期:2025-06-05 发布日期:2025-05-26
通讯作者: ^*lvyafeng@ctgu.edu.cn;yezhang@ibms.pumc.edu.cn
基金资助:
国家自然科学基金(82402176);湖北省自然科学基金面上项目(2025AFB802)

Analysis of key immune-related genes and drug candidates in globoid cell leukodystrophy

LUO Guiyuan¹, LI Yang², ZHANG Ye^1*, LYU Yafeng^2*

1. Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences CAMS,School of Basic Medicine PUMC, Beijing 100005;
2. Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Sciences, China Three Gorges University, Yichang 443000, China

Received:2025-02-20 Revised:2025-03-21 Online:2025-06-05 Published:2025-05-26

摘要/Abstract

摘要： 目的利用克拉伯病患者生成的诱导多能干细胞(iPSCs)衍生的神经干细胞(NSCs)进行分析,鉴定该疾病的关键免疫相关基因及潜在的药物靶点。方法 1)使用GEO2R和Sangerbox分析GLD-NSCs(GSE212512)的转录组数据;2)通过多种方法鉴定与免疫相关的差异表达基因(DEGs);3)利用DAVID进行功能富集和通路分析;4)使用STRING和Cytoscape构建并分析蛋白质-蛋白质相互作用网络;5)通过拓扑分析确定关键免疫相关基因;6)使用DGIdb和DrugMAP数据库筛选潜在的治疗药物;7)使用CB-DOCK2进行分子对接。结果 1)在患者NSCs中鉴定出61个与免疫相关的差异表达基因,GDNF、EGF、KDR、FGF10和MET被确定为关键免疫相关基因;2)鉴定出对这些基因具有高结合亲和力的药物候选物,包括针对GDNF的gentamicin、针对EGF的cetuximab、针对KDR的tivozanib和针对MET的capmatinib。结论预测cetuximab、gentamicin、tivozanib和capmatinib 分别与 EGF、GDNF、KDR 和 MET 具有较高的结合亲和力,提示它们在GLD靶向治疗中的潜在应用价值。

关键词: 球形细胞脑白质营养不良, 克拉伯病, 神经干细胞, 免疫相关基因

Abstract: Objective To identify the key immune-related genes and potential drug targets of Krabbe disease by using neural stem cells(NSCs) derived from induced pluripotent stem cells(iPSCs) generated from patients with Krabbe disease. Methods 1)The transcriptome data of GLD-NSCs(GSE212512) was analyzed using GEO2R and Sangerbox; 2)Differential expression genes(DEGs) related to immunity were identified through various methods; 3)Functional enrichment and pathway analysis were performed using DAVID; 4)The protein-protein interaction network was constructed and analyzed using STRING and Cytoscape; 5)Key immune-related genes were determined through topological analysis; 6)Potential therapeutic drugs were screened using DGIdb and drug MAP data- bases; 7)Molecular docking was performed using CB-DOCK2. Results 1)Sixty-one immune-related DEGs were identified in patient NSCs, with GDNF, EGF, KDR, FGF10, and MET being identified as key immune-related genes; 2)Drug candidates with high binding affinity to these genes were identified, including gentamicin for GDNF, cetuximab for EGF,tivozanib for KDR, and capmatinib for MET. Conclusions The predictions suggest cetuximab, gentamicin, tivozanib, and capmatinib exhibit high binding affinity with EGF, GDNF, KDR, and MET, respectively, indicating their potential application value in GLD targeted therapy.

Key words: globoid cell leukodystrophy, Krabbe disease, neural stem cells, immune-related gene

中图分类号:

R318.04

罗贵元, 李扬, 张业, 吕亚丰. 球形细胞脑白质营养不良的关键免疫相关基因和药物候选物分析[J]. 基础医学与临床, 2025, 45(6): 727-734.

LUO Guiyuan, LI Yang, ZHANG Ye, LYU Yafeng. Analysis of key immune-related genes and drug candidates in globoid cell leukodystrophy[J]. Basic & Clinical Medicine, 2025, 45(6): 727-734.

参考文献 14

[1]	Bradbury AM, Bongarzone ER, Sands MS. Krabbe disease: New hope for an old disease[J]. Neurosci Lett, 2021, 752: 135841. doi: 10.1016/j.neulet.2021.135841.
[2]	Castaneda JA, Lim MJ, Cooper JD, et al. Immune system irregularities in lysosomal storage disorders[J]. Acta Neuropathol, 2008, 115: 159-174.
[3]	Sutter PA, Ménoret A, Jellison ER, et al. CD8+ T cell depletion prevents neuropathology in a mouse model of globoid cell leukodystrophy[J]. J Exp Med, 2023, 220:e20221862. doi: 10.1084/jem.20221862.
[4]	Wang W, Lv YF, Zhang YJ, et al. Generation of a human induced pluripotent stem cell line PUMCi001-A from a patient with Krabbe disease[J]. Stem Cell Res, 2020, 48: 101937. doi: 10.1016/j.scr.2020.101937.
[5]	Lv YF, Wang J, Cao CY, et al. Production and characterization of human induced pluripotent stem cell line(PUMCi002-A) from a Krabbe patient related control to study disease mechanisms associated with GALC mutation[J]. Stem Cell Res, 2022, 65: 102945. doi: 10.1016/j.scr.2022.102945.
[6]	Lv Y, Qin Y, Wang J, et al. Identifying altered developmental pathways in human globoid cell leukodystrophy iPSCs-derived NSCs using transcriptome profiling[J]. BMC Genomics, 2023, 24: 210. doi: 10.1186/s12864-023-09285-6.
[7]	Tian G, Cao C, Li S, et al. rAAV2-mediated restoration of GALC in neural stem cells from Krabbe patient-derived iPSCs[J]. Pharmaceuticals(Basel), 2023, 16:624. doi: 10.3390/ph16040624.
[8]	Shen W, Song Z, Zhong X, et al. Sangerbox: A comprehensive, interaction-friendly clinical bioinformatics analysis platform[J]. Imeta, 2022, 1: e36. doi: 10.1002/imt2.36.
[9]	Ma H, Bell KN, Loker RN. qPCR and qRT-PCR analysis: Regulatory points to consider when conducting biodistribution and vector shedding studies[J]. Mol Ther Methods Clin Dev, 2021, 20: 152-168.
[10]	Sherman BT, Hao M, Qiu J, et al. DAVID: a web server for functional enrichment analysis and functional annotation of gene lists(2021 update)[J]. Nucleic Acids Res, 2022, 50: W216-W221.
[11]	Szklarczyk D, Franceschini A, Wyder S, et al. STRING v10: protein-protein interaction networks, integrated over the tree of life[J]. Nucleic Acids Res, 2015, 43(Database issue): D447-D452.
[12]	Griffith M, Griffith OL, Coffman AC, et al. DGIdb: mining the druggable genome[J]. Nat Methods, 2013, 10:1209-1210.
[13]	Fu C, Jin G, Gao J, et al. DrugMap Central: an on-line query and visualization tool to facilitate drug repositioning studies[J]. Bioinformatics, 2013, 29: 1834-1836.
[14]	Liu Y, Yang X, Gan J, et al. CB-Dock2: improved protein-ligand blind docking by integrating cavity detection, docking and homologous template fitting[J]. Nucleic Acids Res, 2022, 50: W159-W164.

球形细胞脑白质营养不良的关键免疫相关基因和药物候选物分析

Analysis of key immune-related genes and drug candidates in globoid cell leukodystrophy

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