基于糖脂代谢微环境探讨脂肪性肝病“痰浊”的物质基础及化痰方药干预机制

脂肪性肝病严重威胁人类的健康，传统中医药具有独特的防治脂肪肝的理论及治疗策略，从痰论治是其关键之法，然而有关痰邪的物质基础及干预机制仍不完全清楚。基于前期研究成果以及课题组多中心临床研究发现糖脂代谢关键基因Caveolin-1及终末糖基化产物（AGEs）与脂肪肝发病密切相关，我们提出：糖脂代谢紊乱是脂肪肝痰浊微观辨证及治疗的关键，并拟以膜蛋白Caveolin-1、终末糖基化产物受体（RAGE）为切入点，结合CRISPR/cas9技术、代谢组学、斑马鱼高通量分析以及敲基因小鼠平台，多层次、多靶点分析脂肪肝糖脂代谢微环境改变本质以及Caveolin-1、RAGE调控机制；同时通过化痰方药干预治疗，以“药”验“证”反向分析痰浊内涵。阐明脂肪性肝病痰证病机发病基础及靶标调控机制，同时解答化痰治疗原则的现代分子生物机制及作用基础，为脂肪性肝病有效预防及调控寻找新的分子靶点，并为药物开发提供新的思路。

Fatty liver disease (FLD) has become a major public health problem. On aspects of prevention and treatment for FLD, traditional Chinese medicine has unique advantages in both theory and strategy, on basis of syndrome differentiation of phlegm. However, the material basis and intervention mechanism of phlegm are still not fully understood. In the multi-center clinical trial, our previous study discovered a close correlation between the levels of glucolipid metabolism related genes, Caveolin-1 and advanced glycation end products (AGEs), and the pathogenesis of FLD. Therefore, we hypothesize that glucolipid metabolism dysfunction plays a key role in micro-syndrome differentiation and treatment of turbid phlegm in FLD. Based on multiple levels and targets of Caveolin-1 and receptors of advanced glycation end products (RAGE) in FLD, CRISPR/cas9 technique, metabonomics, zebrafish high-throughput analysis and gene knocked-out mice will be used to investigate the regulatory mechanisms and changes of microenviroment of glucolipid metabolism in this project. Moreover, the material basis of turbid phlegm can be reversely analyzed by the effects of formula for resolving phlegm on FLD. By elucidating the mechanisms of the pathogenesis and targeted regulation of phlegm syndrome in FLD and explaining the molecular biological mechanisms and functions of principle of treatment of resolving phlegm, this study will find a novel target for effective prevention and regulation of FLD and provide a new idea for drug discoveries.