非酒精性脂肪性肝炎肝郁脾虚证TLR4/TRIF通路与代谢组学机制研究

项目名称： 非酒精性脂肪性肝炎肝郁脾虚证TLR4/TRIF通路与代谢组学机制研究

项目编号： No.81470190

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 苗宇船

作者单位： 山西中医药大学

项目金额： 73万元

中文摘要： 课题组前期研究证实，胰岛素抵抗（IR）贯穿于非酒精性脂肪性肝炎（NASH）发生发展的始终，脂多糖（LPS）是IR的触发因子。研究发现，肝脏病可出现多种代谢物的变化，炎症和代谢信号存在微妙的平衡，但具体机制尚不清楚。中医理论认为肝主疏泄，脂肪肝发病的基本病机为肝郁脾虚。我们推测NASH中LPS介导的TLR4及其下游的炎性信号转导通路和NASH的代谢组学特征之间的平衡是肝郁脾虚的分子基础。本课题通过建立NASH肝郁脾虚证病证结合的动物模型，并以疏肝健脾法予以反证，分别进行动物实验和细胞培养，观察各组大鼠肝脏和库普弗细胞的TLR4/TRIF通路及其与代谢组学特征之间的平衡关系。在充分体现中医理论的整体观念和辨证论治特点以及方证相应的基础上，拟从整体、器官、细胞、分子和基因水平进行多层次的深入研究，阐明非酒精性脂肪性肝炎肝郁脾虚证的发病机制，揭示肝主疏泄的部分生物学内涵。

中文关键词： 非酒精性脂肪性肝炎；肝郁脾虚证；TLR4/TRIF信号通路；代谢组学；病证结合

英文摘要： Our previous studies have inproved that insulin resistance occurs throughtout the process of the development and progression of nonalcoholic steatohepatitis (NASH), and lipopolysaccharide (LPS) was the trigger factor of IR. The earlier studies have revealed that a variety of metabolites changes can be observed in liver disease. There is a delicate balance between inflammation and metabolism signal, but the specific mechanism is still unclear. In traditional Chinese medicine theory, the liver govern free flow of qi, and the basic pathogenesis of adiposis hepatica is stagnation of liver qi and spleen deficiency. With NASH, we speculate that the banlance between the characteristics of metabolism and TLR4 mediated by LPS with its inflammatory signal transduction pathway may be the molecular basis of the stagnation of liver qi and spleen deficiency. This research intervene the rat model with the combination of disease and syndrome of stagnation of liver qi and spleen deficiency, with the method of soothing the liver and strengthening the spleen . To observe the balance relationship between the TLR4/TRIF signaling pathway and characteristics of metabolism which both in the model rat liver and kupffer cells with animal experiment and cell culture. By in-depth studies at multi-level as body, organ, cell, molecule and gene levels, clarifying the mechanism of pathogenesis of the syndrome of stagnation of liver qi and spleen deficiency for NASH, and reveal part of the biologic connotation of the liver govern free flow of qi.

英文关键词： non-alcoholic steatohepatitis;syndrome of stagnation of liver qi and spleen deficiency;TLR4/TRIF signaling pathway;metabonomics;combination of disease and syndrome