缺氧对抗缺氧中药红景天活性成分代谢、转运与药代动力学及作用的影响及其分子机制

The system 'omics' including genomics, proteomics and metabonomics, and the combination methods of the multi-disciplines consisted of chemical analysis, network technique, molecular biology, drug metabolism and experimental pharmacology are integrally used for studying our project. Based on these combination technologies, the hypoxia animal models and the investigation data, the molecular mechanism of the drug metabolism differences and action targets of the anti-hypoxic traditional Chinese medicine Rhodiola and its active components including flavonoids rhodionin and rhodiosin, are systemically studied under hypoxia condition. Our creative hypothesis of ‘hypoxia condition-drug metabolism-action target-regulatory networks’ in the complicated hypoxic system performed the synchronous synergism is creatively proposed. This research emphasizes on the impacts of the anti-hypoxic drugs under hypoxia on the CYP enzyme subtypes CYP1A1, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2E1 and CYP3A4, and the related transporters in order to elucidate the molecular mechanism of metabolism and pharmacokinetic differences from Rhodiola and its active components. The physiological and pathophysiological changes and the regulatory mechanism are also deeply studied. At the same time, the discovery and identification of the targets related anti-hypoxic action, key nodes or connection points, molecular signaling pathways of and regulatory networks under hypoxia are integrally performed. It is very necessary for investigating the relationship between the structures and bioactivity of anti-hypoxia Rhodiola active components and their metabolites, the proposed metabolic pathways. These explorations produce the strong evidence to discover the novel anti-hypoxia drugs, obtain the useful pharmacokinetic parameters and pharmacodynamic index, and effectively guide the rational use of clinical medicine. This project has an obviously promotion effect on the development of hypoxic pharmacology and pharmacokinetics of anti-hypoxia Rhodiola components. And this project also has a remarkably academic novelty and importance, and enormously potential application values on conquering the mechanism of hypoxia and critical diseases related hypoxia. This program provides novel research idea and combination technical methods for the modern research of traditional Chinese medicine Rhodiola in the complicated extreme system.

本项目综合应用基因组、蛋白质组和代谢组学等系统组学方法、化学分析与分子生物学、药物代谢及中药药理学等多学科新组合技术方法，通过已建立动物缺氧模型和大量前期基础研究结果，重点研究缺氧条件对中药红景天活性成分草质素、苯丙素、红景天素和山柰酚的CYP酶相关亚型CYP1A1, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2E1 和CYP3A4和相关转运体的影响,阐明产生抗缺氧活性成分的体内代谢与药动学差异的分子机制，同时探索发现中药抗缺氧作用的新靶点、分子信号通路和调控网络以及影响缺氧病理生理过程的关键节点和干预机制。并探索抗缺氧活性成分及其代谢产物的结构与活性、主要代谢途径。为发现创新性抗缺氧中药及其活性组分、获得具有实际指导意义的药代参数及药效指标，切实指导临床合理用药提供理论依据。结果对抗缺氧中药红景天及其活性成分的药代、药效和作用机制的物质基础研究有极大促进作用。

本研究课题综合应用基因组、蛋白质组和代谢组学等系统组学方法、化学分析与分子生物学、药物代谢及中药药理学等多学科新组合技术方法，通过已建立动物缺氧模型和大量前期研究结果，重点研究缺氧条件对中药红景天提取物及其主要活性成分红景天苷、红景天素、草质素、草质素苷、槲皮素和山奈酚的相关代谢酶及亚型和相关转运体的影响，阐明产生抗缺氧活性成分的体内代谢与药动学差异的分子机制，同时，探索发现中药抗缺氧作用的新靶点、分子信号通路和调控网络以及影响缺氧病理生理过程的关键节点和干预机制。并研究抗缺氧活性成分及其代谢产物的结构与活性、主要代谢途径。为发现创新性抗缺氧中药及其活性组分、获得具有实际指导意义的药代参数及药效指标，切实指导临床合理用药提供理论依据。结果对抗缺氧中药及其活性成分的发展有极大地促进作用,同时对攻克与缺氧相关重大疾病具有十分重要的学术意义和巨大潜在的应用价值。本研究为抗缺氧中药及其活性成分的药物代谢与活性的物质基础研究开辟了全新的研究思路与关键技术方法。同时对深入理解红景天的中医方药理论，揭示红景天的配伍规律和作用机制，优化红景天制剂工艺，制定质控标准，实现红景天的现代化并走向世界均具有十分的重要意义。.本课题成果已在国外SCI收录杂志发表研究论文6篇，核心刊物论文5篇。核心工作在第18届国际药理学大会和药理相关学术会议做了报告交流。培养出站博士后1人，研究生毕业获得博士学位2人，硕士2人，在职攻读硕士学位3人。本科生毕业获学位3名。培养学术骨干3人。