基于5-HTR/TAS2Rs探讨半夏泻心汤辛开/苦降协同作用的分子机制

经方半夏泻心汤是辛开苦降法的代表方，被广泛用于治疗多种疾病，特别是在治疗消化道疾病方面疗效显著。课题组跟踪国际前沿研究，并利用TCGA、THPA等数生物数据库开展信息分析，发现半夏泻心汤中辛开药物对消化道疾病的治疗作用与5-羟色胺受体(5-HTR)、苦降药物与苦味受体（TAS2Rs）的关系最为密切。且5HTR与TAS2Rs都广泛存在于消化道组织中，二者对胃肠运动、分泌、内脏感觉等有生物效应协同关系。基于中药复方因其成分复杂多样是通过多成分多靶点多环节发挥作用的这一理念，项目组提出科学假说：5-HTR和TAS2Rs的生物协同效应是否在半夏泻心汤辛开苦降的协同机制中扮演了重要的角色？本课题采用CRISPRCas9等正反向遗传学操纵手段结合细胞、类器官、整体等多种评价模型，试图从新的视角阐明半夏泻心汤辛开苦降的协同作用机制，揭示辛开苦降法的科学内涵，研究具有重要的科学价值。

Classical prescriptions Banxia Xiexin Decoction (BXD) is a representative of Xin Kai Ku Jiang method. It is widely accepted by clinical traditional Chinese medicine for treating various diseases and achieving remarkable effects, especially in treating gastrointestinal diseases. Our team followed the international frontier research and carried out data analysis using TCGA、THPA and other databases. We have found that Xin Kai drugs such as Pinellia ternata, Rhizoma zingiberis in BXD have therapeutic effects against gastrointestinal diseases and these effects are closely related with 5- hydroxytryptamine receptor (5-HTR). In addition, Ku Jiang drugs such as Rhizoma zingiberis and Rhizoma coptidis in BXD and bitter taste receptors (TAS2Rs) have important correlations to Xin Kai drugs’ therapeutic effects. Moreover, 5-HTR and TAS2Rs co-localized widely in the gastrointestinal tract tissues, and they have a synergistic relationship with gastrointestinal motility, secretion and visceral sensation. Based on the conceptual idea that mechanism of action for traditional Chinese medicine is mediated by the complex interactions among diverse components in traditional Chinese medicine with the characteristics of multi-components, multi-targets and multi-steps, our team put forward the scientific hypothesis that the biological synergistic effect of 5- HTR and TAS2Rs plays an important role in the synergistic mechanism of Xinkai Ku Jiang in BXD. In our proposed study, we will use gain-of-function and loss-of-function genetic manipulations combined with multiple efficacy evaluation models including small molecules, cell models, organoids, and experimental animal models to clarify the synergistic mechanism of Xin kai Ku Jiang in BXD from a new perspective. Our project will reveal the scientific connotation of Xin Kai Ku Jiang method, and shed light on the mechanistic study of traditional Chinese medicine.