2型糖尿病阴虚证病证结合分子网络模型的构建与初证  

Model Construction and Preliminary Validation of Disease-syndrome Combined Molecular Networks for Type 2 Diabetes Mellitus with Yin Deficiency Syndrome

作　　者：郭航 战丽彬[2] 孙晓霞 陈宁[1] 翁泽斌[1] GUO Hang;ZHAN Libin;SUN Xiaoxia;CHEN Ning;WENG Zebin(School of Traditional Chinese Medicine/School of Integrative Medicine,Nanjing University of Chinese Medicine,Nanjing,210023;Liaoning University of Traditional Chinese Medicine)

机构地区：[1]南京中医药大学中医学院/中西医结合学院,江苏省南京市210023 [2]辽宁中医药大学

出　　处：《中医杂志》2022年第15期1470-1478,共9页Journal of Traditional Chinese Medicine

基　　金：国家重点研发计划(2018YFC1704400);国家中医药管理局2021年岐黄学者支持项目;江苏省研究生科研创新计划(KYCX21_1642)。

摘　　要：目的运用网络生物学方法构建2型糖尿病(T2DM)阴虚证病证结合分子网络,探究其生物学基础,并进行实验验证。方法整合DisGeNET、DrugBank、TTD、MalaCards、OMIM、CTD、GEO数据库信息,获得T2DM疾病相关基因。运用社团发现算法将STRING数据库中的PPI网络划分为拓扑模块,将疾病相关基因映射至模块中获得T2DM疾病模块。将从SymMap、HPO、GeneCards数据库获取的阴虚证症状对应基因映射至疾病模块,从而筛选出T2DM阴虚证病证结合模块。再通过治疗T2DM西药对应靶点与模块靶点对应关系,以及滋阴方剂靶点与病证结合模块的相关性分析,验证结果的可靠性。借助Metascape平台对分子网络进行GO和KEGG富集分析。最后采用温热伤阴法构建病证结合小鼠模型,分为正常对照组、单纯阴虚证组、2型糖尿病组、2型糖尿病阴虚证组,取血清和下丘脑组织对预测的关键靶点进行验证。结果筛选出1514个T2DM疾病相关基因以及1547个T2DM阴虚证相关基因,确定了19个与T2DM密切相关的疾病模块,并将其中的7个与阴虚证相关的模块定义为T2DM阴虚证病证结合模块。经过西药靶点、滋阴方剂的验证,最终确立T2DM阴虚证病证结合核心模块Mem3、5、39。富集分析揭示生物学基础可能涉及糖脂代谢紊乱、免疫炎症、内分泌紊乱等诸多病理过程。对Mem5及Mem39的核心靶点白细胞介素6(IL-6)及鸟嘌呤核苷酸结合蛋白q多肽(GNAQ)介导通路相关蛋白即异源三聚体嘌呤核苷酸结合蛋白(Gq)、磷脂酶Cβ1(PLCβ1)、磷脂酶Cβ3(PLCβ3)蛋白进行验证,结果提示2型糖尿病阴虚证组小鼠血清中IL-6水平及下丘脑Gq、PLCβ1蛋白表达显著高于正常对照组和2型糖尿病组(P<0.05或P<0.01)。结论G蛋白信号转导系统、糖脂代谢、免疫功能、炎症反应、内分泌紊乱等是2型糖尿病阴虚证核心生物学过程。Objective To construct the disease-syndrome combined molecular network for type 2 diabetes mellitus(T2 DM)using network biology approaches,and to explore its biological basis and validate it through experimental data.Methods The DisGeNET,DrugBank,TTD,MalaCards,OMIM,CTD,and GEO databases were integrated to obtain T2 DM-related genes.The PPI network in the STRING database was divided into topological modules using the algorithm for community discovery,and the disease-related genes were mapped into the modules to obtain the disease module of T2 DM.The genes corresponding to the symptoms of yin deficiency syndrome obtained from SymMap,HPO,and GeneCards databases were mapped into the disease module,so as to get the disease-syndrome combined module for T2 DM with yin deficiency syndrome.Furthermore,the results were verified through the corresponding relationship between the T2 DM western medicine targets and the module targets,and the correlation analysis between nourishing formula targets and the disease-syndrome combined module.GO and KEGG enrichment analysis was performed for the molecular networks based on the Metascape platform.Finally,the warm-heat damaging yin method was used to construct the disease-syndrome combined mice model,which was divided into normal control group,yin deficiency syndrome group,T2 DM group,and T2 DM with yin deficiency syndrome group,and the serum and hypothalamic tissues were taken to validate the predicted key targets.Results Totally,1514 T2 DM-related genes and1547 T2 DM with yin deficiency syndrome-related genes were obtained,and 19 disease modules closely related to T2 DM were identified,of which 7 modules related to yin deficiency syndrome were defined as the disease-syndrome combined modules for T2 DM with yin deficiency syndrome.Through validation by western medicine targets and nourishing yin formulas,Mem3,5,and 39 as the core disease-syndrome combined modules for T2 DM with yin deficiency syndrome were finally established.The enrichment analysis revealed that the biological basi

关 键 词：2型糖尿病 阴虚证 网络生物学 病证结合模块 

分 类 号：R259[医药卫生—中西医结合]