基于中药-机体双重代谢网络的大明胶囊治疗高脂血症的药效物质基础与作用机制研究

Hyperlipemia is a kind of complex lipid metabolism disorder caused by multiple factors. Due to their serious side effects, the current antilipemic drugs on market generally are not suitable for a long-term treatment. Daming capsule, a Chinese medicine formula, has been proved to have an advantage of high efficiency and low toxicity in previous clinical trial. However, its material basis and underlying mechanism of treatment for hyperlipemia remains unknown. In this project, we aim to uncover its material basis and underlying action mechanisms of treating hyperlipemia based on the interactions between exogenous and endogenous metabolic networks. Firstly, the exogenous metabolic network of Daming capsule will be built through serum pharmacochemistry, tissues distribution, and excretion studies. On the basis of the exogenous metabolic network, potentially effective components of Daming capsule will be obtained by establishing its PK-PD model. Then the underlying action mechanism and theraprutic targets of Daming capsule on regulating endogenous metabolic network in hyperlipemia model will be clarified by metabolomics study. Finally, the material basis of Daming capsule will be uncovered through correlation analysis between the potentially effective components and therapeutic targets. Most importantly, this project will deepen the cognition on scientific connotation of Daming capsule, offer significant scientific basis for research and development of effective and safe new drugs for treating hyperlipemia with independent intellectual property rights, and provide novel insights into researches on material basis and action mechanism of Chinese medicine through multidisciplinary and high-throughput strategy.

高脂血症是多因素导致的综合性脂质代谢紊乱疾病，现有药物由于其严重不良反应而不能长期应用。中药复方大明胶囊的前期临床试验已经证实其具有疗效好、不良反应小的优势，但其药效物质基础与作用机制仍不明确。本项目拟从大明胶囊外源性代谢网络与高脂血症机体内源性代谢网络相互作用的角度出发，首先通过血清药物化学、组织分布和排泄研究构建大明胶囊的外源性代谢网络，在此基础上建立大明胶囊的药代动力学-药效动力学模型并获得其潜在有效成分；然后通过代谢组学技术阐明大明胶囊调控高脂血症机体内源性代谢网络的作用机制并获得其药效靶标；最后通过对药效靶标和潜在有效成分的关联度分析，揭示大明胶囊治疗高脂血症的药效物质基础。本项目可深化对大明胶囊的科学内涵认识；为研制出疗效好、不良反应小、具有自主知识产权的治疗高脂血症的新药提供重要科学依据；建立多学科交叉的高通量研究策略为中药的药效物质基础与作用机制研究提供新的思路。

高脂血症是多因素导致的综合性脂质代谢紊乱疾病，现有药物由于其严重不良反应而不能 长期应用。中药复方大明胶囊的前期临床试验已经证实其具有疗效好、不良反应小的优势，但其药效物质基础与作用机制仍不明确。本项目从大明胶囊外源性代谢网络与高脂血症机体内源性代谢网络相互作用的角度出发，首先通过血清药物化学、代谢组学以及模式识别分析研究构建大明胶囊的外源性代谢网络，并获得其药效物质基础；然后通过尿液以及血清代谢组学技术阐明大明胶囊调控高脂血症机体内源性代谢网络的作用机制并获得其药效靶标。在此基础上，本项目还对大明胶囊药效物质基础中的重要成分，芦荟大黄素，进行了降血脂、降肝脂药效研究，并通过尿液和血清代谢组学阐明其作用机制，该成分与大明胶囊一样也同时具有保护心脏的作用，进一步证明芦荟大黄素是大明胶囊的物质基础。本项目深化了对大明胶囊的科学内涵认识；建立多学科交叉的高通量 研究策略为中药的药效物质基础与作用机制研究提供新的思路，并研制出疗效好、具有自主知识产权的治疗高脂血症的潜在新药，芦荟大黄素。