Page 66 - 南京医科大学自然版

南京医科大学学报（自然科学版） 第44卷第6期
·802 · Journal of Nanjing Medical University（Natural Sciences） 2024年6月

·临床研究·

基于线粒体自噬相关基因的哮喘亚型鉴定及预测模型构建研究

马晴晴，顾圣玮，王红玉，姚 欣，曾晓宁 *
南京医科大学第一附属医院呼吸与危重症医学科，江苏 南京 210029

［摘 要］ 目的：研究哮喘中线粒体自噬相关基因（mitochondrial autophagy⁃related gene，MRG）表达情况、构建疾病预测模型，
根据MRG特征对哮喘进行分型并挖掘可能的潜在靶标与治疗药物。方法：基因表达综合数据库中获得哮喘气道上皮转录组
学数据，筛选出差异表达MRG，并在哮喘小鼠气道上皮及白介素（interleukin，IL）⁃13刺激的小鼠原代气道上皮细胞模型中行免
疫组化验证；运用机器学习算法构建哮喘预测模型，根据MRG表达谱分型，基因本体论及京都基因与基因组百科全书分析生
物学功能及相关信号通路差异；药物基因组学数据库筛选可能的靶向药物。结果：哮喘患者MRG整体表达较健康受试者显著
升高，差异最显著基因为线粒体外膜转位酶5（translocase of outer mitochondrial membrane 5，TOMM5），其在哮喘患者、哮喘小鼠
气道上皮细胞及IL⁃13刺激的小鼠原代上皮细胞模型中表达均上调；22个MRG中筛选出7个疾病最相关特征基因（TOMM5、
FUN14 结构域蛋白 1、线粒体外膜转位酶 22、自噬接头受体蛋白 1、磷酸甘油酸变位酶 5、线粒体融合蛋白 2 及核糖体蛋白
S27a），并以此构建哮喘预测模型，受试者工作特征曲线评估显示预测性能良好；共识聚类分析将哮喘分为2个亚型，两型在基
因表达及通路富集方面均存在显著差异；不同分型靶向小分子药物的预测结果分别为XMD8⁃92和Verrucarin⁃A。结论：上述7个
MRG可作为哮喘预测的有效分子标志物，研究结果有望为患者疾病分型及个体化治疗提供新的参考依据。
［关键词］ 哮喘；线粒体自噬；预测模型；亚型
［中图分类号］ R562.25 ［文献标志码］ A ［文章编号］ 1007⁃4368（2024）06⁃802⁃10
doi：10.7655/NYDXBNSN240152

Asthma subtypes identification and prediction model establishment based on

mitochondrial autophagy⁃related genes
MA Qingqing，GU Shengwei，WANG Hongyu，YAO Xin，ZENG Xiaoning *
Department of Respiratory & Critical Care Medicine，the First Affiliated Hospital of Nanjing Medical University，
Nanjing 210029，China

［Abstract］ Objective：This study investigated the expression of mitochondrial autophagy ⁃ related genes（MRG）in asthma to
establish a novel model for disease prediction，and also identified asthma subtypes based on the MRG to figure out the potential
molecular targeted drugs. Methods：The data of asthmatic airway samples were obtained from gene expression omnibus data base.
Differentially expressed MRGs were screened and validated in asthmatic mice or primary airway epithelial cells challenged by
interleukin（IL）⁃ 13 with immunohistochemistry so as to build a model for disease prediction using machine learning algorithms.
According to the different MRG expression pattern，two subtypes of asthma were defined，and biological functions and signaling
pathways were investigated by gene ontology（GO）and kyoto encyclopedia of genes and genomes（KEGG）analysis to find out the
potential agents through a connectivity map database. Results：MRG expression in asthma patients was significantly increased
compared with those in healthy subjects. Among these genes，translocase of outer mitochondrial membrane 5（TOMM5）was found to be
the top differentially expressed MRG，which were up⁃regulated both in the airway epithelium of asthma patients or asthmatic mice and
the primary airway epithelial cells stimulated by IL⁃13. In 22 MRGs，seven genes［TOMM5，FUN14 domain containing 1，translocase of
outer mitochondrial membrane 22，sequestosome 1，phosphoglycerate mutase 5，mitofusin⁃2，ribosomal protein S27a］were screened to
establish a model for disease prediction for its good performance exhibited by a receiver operating characteristic curve assessment in
asthma. Through a consensus cluster analysis，two subtypes of asthma were classified considering the differences of gene expression
and pathway enrichment. The predicted small molecule agents targeting these two subtypes were XMD8 ⁃ 92 and Verrucarin ⁃ A，

［基金项目］ 国家自然科学基金（81970016，82311530108）
∗
通信作者（Corresponding author），E⁃mail：zeng_xiao_ning@hotmail.com