靶向花生四烯酸代谢-炎症网络解析血府逐瘀汤治疗创伤性颅脑损伤的调控机制

Based on the idea from Chinese theory “Cong Yu Lun Zhi”, TBI treatment with Xuefu Zhuyu decoction (XFZY) was supported by much clinical evidence, but the corresponding mechanisms of its multi-target action remains to be elucidated. Our previous animal experiments confirmed that XFZY down-regulated the levels of arachidonic acid (AA), TNF-α and IL-1β via inhibiting PI3K/Akt/mTOR signal pathway in the brain regions following TBI. Based on this clue, our recent experiments of metabolomics combined with bioinformatics analysis showed that TBI treatment with XFZY referred to the regulation of AA metabolism-inflammatory cascade reaction. Hence, we proposed a hypothesis that XFZY performed TBI treatment through target regulation of AA metabolism-inflammatory reaction. To confirm this scientific hypothesis, under the guidance of TCM holism and systemic biology, this project aims to use quantitative proteomics-metabolomics techniques to capture the key molecular clusters referred to AA metabolism-inflammatory reaction after XFZY treatment following TBI in a rat model; to apply bioinformatics analysis methods to build the network map of regulating AA metabolism-inflammation, and finally to utilize molecular biological methods to verify the above network map according to in vivo and in vitro studies. This plan will provide the new perspective for the effects of network regulation and modern scientific understanding after XFZY treatment following TBI based on the Chinese theory “Cong Yu Lun Zhi”.

血府逐瘀汤从瘀论治创伤性颅脑损伤（TBI）获得了多项临床证据支持，但其多靶点作用机制有待阐明。我们前期已证实：血府逐瘀汤抑制TBI大鼠脑区PI3K/Akt/mTOR信号通路，下调花生四烯酸（AA）及其介导的TNF-α和IL-1β水平。以此为线索，我们最近基于代谢组学结合生物信息学研究，捕获到血府逐瘀汤治疗TBI涉及AA代谢-炎症的靶标证据。据此提出假说：血府逐瘀汤通过调控AA代谢-炎症网络治疗TBI。为验证该假说，本项目拟以中医整体观和系统生物学为指导，应用定量蛋白质组学-代谢组学方法明确血府逐瘀汤调控AA代谢-炎症反应治疗TBI大鼠的分子靶标群；利用生物信息学手段构建上述多靶点、多信号通路参与的网络图谱；结合体内外实验，采用分子生物学方法最终证实这一网络；以揭示血府逐瘀汤靶向AA代谢-炎症反应治疗TBI的网络调控机制。本项目将为解析血府逐瘀汤从瘀论治TBI的网络效应及科学内涵提供新视角。

血府逐瘀汤从瘀论治创伤性颅脑损伤获得了多项临床证据支持，但其多靶点作用机制有待阐明。本项目基于定量蛋白质组学-代谢组学，结合生物信息学研究，以主要捕获血府逐瘀汤治疗创伤性颅脑损伤涉及花生四烯酸代谢-炎症的靶标证据，为深入揭示血府逐瘀汤对花生四烯酸代谢-炎症网络的调控作用提供创新基础证据。在中医整体观和系统生物学的指导下，我们应用网络药理学-定量蛋白质组学-代谢组学联合检测手段，构建了血府逐瘀汤对创伤性颅脑损伤大鼠实现治疗作用的时空定量蛋白组学-代谢组学网络图谱。血府逐瘀汤通过调节脑组织氨基酰基tRNA的生物合成、丁酸代谢、不饱和脂肪酸的生物合成、酮体的合成和降解、半胱氨酸和蛋氨酸代谢、嘌呤代谢和精氨酸和脯氨酸代谢等形成的蛋白-代谢网络治疗创伤性颅脑损伤，其中通过调节精氨酸和脯氨酸代谢改善神经炎症。并率先从网络调控花生四烯酸代谢-炎症反应角度揭示血府逐瘀汤通过调节花生四烯酸代谢中的环氧化酶途径发挥抗炎效应。同时，基于血府逐瘀汤吸收成分，创制了一种酪氨酸衍生装载苦杏仁苷水凝胶，其通过局部注射显著减轻了模型大鼠神经炎症反应。本项目将有助于阐释血府逐瘀汤抗炎治疗创伤性颅脑损伤多靶点和多信号通路调控的分子机制，为从瘀论治创伤性颅脑损伤的临床应用提供创新基础理论依据。