基于PI3K/Akt信号通路调控炎症因子网络探讨银屑灵复方治疗银屑病的分子机制

Psoriasis is a chronic inflammatory skin disease. PI3K/Akt signaling pathway has close correlation with the pathogenesis of psoriasis, which regulates cell proliferation, differentiation and apoptosis. Yinxieling formula (YXLF) is prescribed by Prof. Guowei Xuan, who is a famous TCM physician in China. YXLF has been clinically applied for twenty years and shows good curative effects. Multiple compounds in YXLF have anti-inflammatory activities and can regulate the expressions of several inflammatory factors. Therefore, we propose a hypothesis that the regulation of network of inflammatory factors by PI3K/Akt signaling pathway would be the molecular mechanism of YXLF. In this proposal, will adopt systems pharmacological approaches to construct the network of inflammatory factors. Then the interactions between compounds of YXLF and cellular targets will be predicted by molecular modeling and validated by Octet Red96 Automated Biosensor. By using network centralities, network efficiency and network flux as indicators, the influence of compounds and YXLF on the network can be quantitatively evaluated, so that to screen out key compounds. Finally, the compound-target interactions and regulation of network of inflammatory factors will be validated by in vitro cell experiments. The results of this study will elucidate the molecular mechanism of YXLF at the molecular and systems levels, and promote the application and further development of YXLF.

银屑病是一种常见的炎症性皮肤疾病，PI3K/Akt信号通路调控细胞增殖、分化和凋亡，参与炎症过程，是银屑病致病机制的关键一环。近年来课题组围绕国医大师禤国维教授的验方银屑灵复方开展基础研究，发现复方及多种活性成分具有抗炎活性，并能调节多种炎症因子的表达。本研究根据银屑病与炎症的密切关系及前期研究结果，提出“银屑灵复方基于PI3K/Akt信号通路调控炎症因子网络可能是其治疗银屑病的分子机制”这一科学假说。为验证其科学性，本研究首先运用系统药理学方法构建PI3K/Akt信号通路调控的炎症因子网络，采用分子模拟预测复方成分与网络中多个靶点的相互作用，并用分子相互作用仪验证，明确关键活性成分及靶点；再利用已开发的基于通路网络的药效评价方法评估复方和关键活性成分的药效；最后采用细胞实验验证。课题的完成将在分子和系统水平阐释银屑灵复方治疗银屑病的作用机制，促进验方的推广及进一步开发。

银屑病是一种具有多基因遗传背景的炎症性皮肤疾病，PI3K/Akt信号通路调控细胞增殖、分化和凋亡，参与炎症过程，是银屑病致病机制的关键一环。本项目运用系统药理学方法构建PI3K/Akt信号通路调控的炎症因子网络，涵盖11个炎症因子（TNF-α、IL-1β、IL-6、IL-10、IL-12、IL-17A、IL-23、IL-27、IFN-γ、NO和PGE2），网络分析发现了通路中的关键靶点，预测了银屑灵复方成分与网络中多个靶点的相互作用；采用HaCaT细胞增殖模型及LPS刺激HaCaT细胞炎症模型筛选了银屑灵复方抑制角质细胞增殖及炎症的关键活性成分，发现银屑灵复方及其活性成分可有效上调多种抑炎因子及下调多种促炎因子的表达，并能降低PI3K/Akt信号通路中关键蛋白PI3K、Akt、NF-κB、MAPK1、TNF-α、IL-6的表达；从系统水平揭示了银屑灵复方可能是通过调节PI3K/Akt信号通路及其上下游的靶点，从而对炎症水平进行综合调控，进而发挥治疗银屑病的功效。本项目的研究结果为促进银屑灵复方的临床推广及进一步开发提供了理论依据。