基于网络药理学的丹七片治疗心肌缺血诱导脂质代谢紊乱PPARs/RXR-CYP2C9通路的药-效机制研究

Our early experiments demonstrated for the first time that the pure myocardila ischemia can reversely induce the peripheral blood lipid metabolism disorders . As an effective formula for clinical myocardial ischemia treatment,Danqi Pill should have reulatory roles on lipid metabolism, the efficacy has not been reported yet . This project intends to use ADME/T method , considering the oral bioavailability, absorption , transport , metabolism and other sectors of the formula, combining with Drug-Cipher technology to predict the potential drug targets for Danqi Pill according to its compounds.Then combining with highthrought anlalysis with HTS/HCS to screen direct mapping relationships of the compounds -targets. By applying KEGG protein interaction network technology, considering the hFABP-PPARγ/δ-RXR-CYP2C9 lipid pathways as a starting point, to build compounds- targets molecule network of the Danqi Pill; the overall regulation of Danqi Pill for target molecules of the network are validated in vitro. Our purpose is to determine the mechanism of Danqi Pill act on the myocardial ischemia with lipid disorders on two levels from the active compounds to drug targets , thus revealing synergies , multi-channels, multi-pathways network effect of the formula in traditional Chinese medicine. This project will provide a new methods for development of new drug and its pharmacology evaluation . It also can be applied to the compound optimization, formula refined, and secondary development of new drugs.

前期实验首次证实单纯心肌缺血能够逆向诱导外周血脂代谢紊乱。作为治疗心肌缺血确有疗效的复方，丹七片应该对脂质代谢紊乱也具有调控作用，该药效未见报道。本课题拟采用ADME/T方法，综合考虑该复方的口服利用度、吸收、转运、代谢等环节；运用Drug-Cipher技术，以丹七片成分为模板，虚拟预测潜在药靶群；结合高通量HTS/HCS分析方法，筛选药-靶直接对映关系；联合应用KEGG与蛋白质交互作用网络技术，以hFABP-PPARγ/δ-RXR-CYP2C9脂质通路为切入点，构建丹七片成分对映靶标群之间的上下游关系与药-靶分子网络；离体细胞验证中药成分调控药靶分子网络的整体作用机制，从作用靶点到起效成分两个层面确定丹七片治疗心肌缺血脂质紊乱的关联分子网络与物质基础，进而揭示中药复方协同增效、多点微调的多途径、多靶点整体网络调控机制，为中药新药的研发与药理药效评价，复方优化、精制与二次开发提供新的思路。

前期课题组实验首次证实单纯心肌缺血能够逆向诱导外周血脂代谢紊乱。作为治疗心肌缺血确有疗效的复方,丹七片应该对脂质代谢紊乱也具有调控作用,该药效未见报道。本课题采用ADME/T方法,综合考虑该复方的口服利用度、吸收、转运、代谢等环节;运用Drug-Cipher技术,开发了首个用于中药分子作用机制研究的生物信息学工具BATMAN-TCM，此后我们以丹七片成分为模板,虚拟预测丹七片潜在的药靶群;联合应用KEGG与蛋白质交互作用网络技术,以hFABP-PPARγ/δ-RXR-CYP2C9脂质通路为切入点进行丹七片药理机制验证。整体动物和离体细胞模型证实,丹七片能有效改善AMI后左心室功能下降,减少炎细胞浸润及增强ATP及心肌能荷,促进游离脂肪酸的摄入及增强β氧化效率,提示丹七片能够改善AMI后脂质代谢紊乱的作用机制。同时,丹七片调控糖代谢的机制除与促进心肌组织中葡萄糖摄取及GLUT4的表达之外,还能够通过促进PFK的表达来促进糖酵解;同时也能够抑制p-GSK3β及p-GS蛋白表达从而抑制糖原的合成,加速糖代谢,其信号转导通路与调控PI3K/AKT-HIF1α相关。基于此课题,已发表SCI论文13篇,中文4篇,在投SCI文章1篇,均标有课题编号。本人在2018年成功入选国家自然基金优青项目，北京市科技新星，以及中华中医药学会青年托举工程，培养研究生1名。本课题初步揭示了中药丹七片调控药靶分子网络的整体作用机制,进而揭示中药复方协同增效、多点微调的多途径、多靶点整体网络调控机制,为中药新药的研发与药理药效评价,复方优化、精制与二次开发提供新的思路。