围绕GLP1-Arginine-AGE/RAGE轴构建探针组学方法探索大柴胡汤异病同治的效应机制

临床研究已证实大柴胡汤对哮喘和糖尿病均有疗效，但其“异病同治”的效应机制尚不明确。针对GLP1-Arginine-AGE/RAGE（GAA）轴的异常活化与两种疾病的密切关联，课题组前期发现大柴胡汤可激活GLP1R的表达、调控L-精氨酸代谢来影响GAA轴的活化。因此，本项目提出大柴胡汤可能是通过GAA轴，依赖功能代谢物、受体和酶等多靶点实现对哮喘和糖尿病异病同治。拟开展以下研究：①明晰大柴胡汤化学成分与靶组织暴露特征，结合亲和质谱技术和受体生物传感器发现其作用于GAA轴的活性组分；②围绕GAA轴构建探针组学方法发现疾病相关功能代谢组，通过整合分析多组学数据构建靶点互作网络，发现大柴胡汤的潜在作用途径；③围绕GAA轴从ADMA介导的胰岛素信号通路和IL-33介导的免疫炎症反应，解析大柴胡汤异病同治的效应机制。本研究为解析中药复方异病同治的科学内涵提供方法支撑，将促进靶向GAA轴的创新中药研发。

Clinical researches have confirmed the curative effect of Dachaihu-decoction on asthma and type 2 diabetes. However, the action mechanism of "homotherapy for heteropathy" is still unclear. It has been confirmed that abnormal activation of the GLP1-Arginine-AGE/RAGE (GAA) axis is closely associated with asthma and type 2 diabetes. Our previous research found that Dachaihu-decoction could activate GLP1R and regulate the metabolism of arginine to affect the activation of GAA axis. Based on the above findings, this project is aim to carry out the following research: Firstly, UPLC-QTOF/MS is used to clarify the composition of chemome in Dachaihu-decoction and to profile their spatial distribution characteristics in target tissues. With the use of affinity mass spectrometry technology and receptor biosensor, bioactive chemome in Dachaihu-decoction will be further screened out. Secondly, the mass spectrometry-based chemical probes will be constructed according to the GAA axis to find the functional metabolome which plays the role of "homotherapy for heteropathy". With the integration of multi-omics data, a functional correlation network will be constructed to provide clues for exploring the potential action of Dachaihu-decoction. Thirdly, based on the above clues, the detail mechanisms of Dachaihu-decoction for the treatment of asthma and type 2 diabetes will be revealed through the GAA axis. This study will provide a methodological support for the analysis of the scientific connotation of “homotherapy for heteropathy” in traditional Chinese medicine (TCM), promoting the secondary development of classical TCM formula.