从PI3K-Akt-mTOR通路动态调控研究血府逐瘀汤从瘀论治创伤性脑损伤的分子机制

The anticoagulant/procoagulant treatment of Traumatic brain injury (TBI) constitutes a contradiction. The treatment of TBI by Xuefu Zhuyu Decoction reflects the essence of blood stasis in Traditional Chinese Medicine. We have presented evidence that the role of Xuefu Zhuyu Decoction in the treatment of TBI in rat model by inhibiting the PI3K-Akt-mTOR signaling pathway, which was as an anti-inflammatory agent in acute stage and as activation agent for up-regulated protein in chronic stage. Therefore, we speculated that the mechanism of Xuefu Zhuyu Decoction in the treatment of TBI involves the whole dynamic regulation of PI3K-Akt-mTOR pathway. In order to elucidate its potential regulation mechanism, we use targeted metabolomics and bioinformatic analysis methods for animal and cellular experiments to analyze Xuefu Zhuyu Decoction from the holistic concept of traditional Chinese medicine; in order to reveal its blood stasis regulation spectrum, we use the method of molecular biology to validate regulatory pathways of PI3K-Akt-mTOR. This study will provide a new perspective to reveal therapeutic mechanism of Xuefu Zhuyu Decoction for treating TBI based on blood stasis.

创伤性脑损伤（TBI）的促凝/抗凝是临床治疗的矛盾焦点。血府逐瘀汤从瘀论治TBI体现止血/抗凝的共存疗效。我们前期发现：全方治疗TBI大鼠模型，通过以靶向PI3K-Akt-mTOR信号通路为核心，对急性出血期通过抑制效应发挥脑内的抗炎作用；在慢性凝血期则发挥激活作用上调突触蛋白水平。据此推测：血府逐瘀汤治疗TBI的作用机制涉及PI3K-Akt-mTOR通路的全程动态调控。为验证该假说，本项目拟基于中医整体观，结合动物和细胞实验，运用靶向代谢组学-生物信息学分析方法，解析血府逐瘀汤靶向PI3K-Akt-mTOR通路对TBI急性期化“有形之瘀”和慢性期活“无形之瘀”的动态调控机制；在此基础上，借助分子生物学及基因工程技术验证代谢组学-生物信息学构建的调控途径；以揭示血府逐瘀汤靶向PI3K-Akt-mTOR“从瘀论治”TBI的动态调控机制。本研究将为揭示血府逐瘀汤从瘀论治TBI提供新视角。

创伤性脑损伤（TBI）的促凝/抗凝是临床治疗的矛盾焦点。血府逐瘀汤从瘀论治TBI体现止血/抗凝的共存疗效。我们前期证实血府逐瘀汤治疗TBI大鼠模型，通过以靶向PI3K-Akt-mTOR信号通路为核心，对急性出血期通过抑制效应发挥脑内的抗炎作用；在慢性凝血期则发挥激活作用上调突触蛋白水平。据此推测：血府逐瘀汤治疗TBI的作用机制涉及PI3K-Akt-mTOR通路的全程动态调控。本项目从中医整体观，结合动物行为学/分子生物学和细胞实验，运用靶向代谢组学-生物信息学分析方法，解析了血府逐瘀汤靶向PI3K-Akt-mTOR通路对TBI急性期化“有形之瘀”和慢性期活“无形之瘀”的动态调控机制主要涉及花生四烯酸代谢通路；并代谢组学-生物信息学构建的调控途径即花生四烯酸代谢；揭示了血府逐瘀汤靶向PI3K-Akt-mTOR“从瘀论治”TBI的动态调控机制，为血府逐瘀汤从瘀论治TBI提供新视角。