肾纤维化是多个信号通路控制的进行性病理学过程，其治疗需针对多个环节进行动态调节。课题组前期研究揭示大黄酸和姜黄素是治疗肾纤维化临床验方—补肾活血方的主要药效成分，然而两者联用对疾病网络的精准调节机制及最佳配伍仍待阐明。本项目在前期工作基础上，拟通过文献挖掘构建肾纤维化核心通路网络，并应用细胞代谢组学方法筛选生物标志物，构建(代谢通路)蛋白-代谢物网络；进而整合两网络构建大黄酸/姜黄素-(信号通路)蛋白-(代谢通路)蛋白-代谢物网络，应用常微分方程组模拟该网络及两组分扰动下的网络动力学行为。最后通过分子药理学及靶向代谢组学技术定量检测NRK-49F细胞中关键通路蛋白及代谢物以验证上述网络模拟结果。从信号通路—代谢通路整合角度定量阐明两组分协同的分子机制，明确两组分最佳配伍并在动物模型上评价疗效。发展基于疾病网络的多组分(组合)药物协同作用的新方法、新策略，为补肾活血方的二次开发提供科学依据。

Renal fibrosis is a progressive pathological process which is controlled by multiple signaling pathways. The treatment needs dynamic regulation in multiple pathways. Our previous studies revealed that the rhein and curcumin were the main active components from clinic prescription of Bushen Huoxue Decoction in treating renal fibrosis, but their accurate regulation theory to disease network and the best concentration compatibility remain to be elucidated. On the basis of our preliminary work, the core pathway network in renal fibrosis will be constructed through literature survey and further investigation in this project. Meanwhile, biomarkers are screened and identified by cell metabolomics. Then a (metabolic pathway) protein - metabolite network will be established with the obtained biomarkers. And then it will be integrated with the core pathway network to establish a rhein/curcumin - (signaling pathway) protein - (metabolic pathway) protein - metabolite network. Furthermore, ordinary differential equations are used to simulate the dynamic response of the core biochemical network in renal fibrosis before and after a two-component disturbance. Finally, molecular pharmacology and targeted metabolomics will be used to detect the concentration of proteins and metabolites in the key pathway in NRK-49F cells to validate the results of network simulations. This project aims at elucidating the molecular mechanism of two chemical components by the way of integrating signal transduction pathway with the metabolic pathway, determining the two-component optimal concentration compatibility, developing new methods and strategies for the multi-component drug discovery based on disease networks, and providing a scientific basis for the secondary development of Bushen Huoxue prescription.