基于组学和斑马鱼模型的缺氧关键代谢途径、调控网络及相关活性物质的分析表征和确证

Hypoxia is a frequently pathophysiological condition or process in which the body, tissue or cell are deprived of adequate oxygen supply. Many diseases, including cardiovascular disease, stroke, asthma, Parkinson, Alzheimer and cancer, are related with the progress of hypoxia. Furthermore, hypoxia also occurs in healthy people when they ascend to high altitude or dive deep underwater. Hypoxic preconditioning (HPC), a strategy of intrinsic cytoprotection developed in biological evolution, is motivated by repetitive exposure of the organism, tissue and cell to a nonfatal hypoxia. Recent our study showed that the brain extracts from HPC mice could significantly improve the anti-hypoxic abilities for normal mice, tissues and cells. . The multidisciplinary, novel technology and methods from the systemic omics such as the transcritomics, proteomics and metabolomics, chemical analysis, molecular biology, stechiometry drug metabolism and experimental pharmacology are combined and used to study and character the key genes, proteins and active small molecular metabolites and the metabolic pathways for the hypoxic damage in the zebrafish hypoxic models constructed by our lab. The main aim of the project is to study the endogenous anti-hypoxic substances, the metabolites, the key junctions, main metabolic pathways and the regulatry actions for patho-physiological process affected by hypoxia. The endogenous key molecules including the hub genes, proteins and active small molecular metabolites, the key metabolic pathways and regulatory networks related the hypoxic injury shall be investigated and validated with comprehensive and detailed ranges. We focus on the main actions, mechanism and relationship between the structure and activity from the endogenous anti-hypoxic active substances and their metabolites, the hub metabolic nodes and pathways, and the regulatory networks produced from the zebrafish hypoxic models. We also hope to reveal the pathophysiological essence of the endogenous anti-hypoxic active substances, metabolic nodes and pathways, and the regulatory networks produced from the hypoxic injure and adaptation process. The high-throughput, high-resolution and complex data processing techniques are also used to identified and analyzed by the structural identification techniques combined with multivariate statistical and stechiometry methods. The endogenous active metabolites and biomarkers from the hypoxic materials are screened and identified. The action mechanism and regulation networks of the anti-hypoxia small molecular substances in hypoxic damage are also investigated. Meanwhile, the key regulation molecules, the specified biomarkers and/or drug action targets with our independence and intellectual property rights are screened, identified and validated. The novel candidates of anti-hypoxia will also be discovered and developed. It is of great academic significance and potential application values for our study to uncover the nature of hypoxic damage, and cure the critical diseases related the hypoxia.

本项目综合应用组学技术、化学分析、生物信息学、分子生物学、药物代谢及实验药理学等多学科新技术方法，通过我们已建立的斑马鱼缺氧损伤和适应模型，对缺氧损伤的关键基因、蛋白和内源性小分子代谢产物进行系统的分析和结构表征。对缺氧损伤相关内源性分子、代谢途径和关键调控网络进行全面细致的研究，确证已发现的内源性抗缺氧活性物质及其代谢物的结构与活性、关键节点和3个关键代谢途径以及对低氧生理病理过程的网络调控作用，并进一步探索这些内源性抗缺氧活性物质在缺氧损伤适应中的关键作用及机制，揭示缺氧适应的生理病理学本质。发现和鉴定新的特异性缺氧标志物和抗缺氧作用靶标，筛选抗缺氧物质，鉴定、表征和确证具有自主知识产权的抗低氧的调节活性物质和药物，为发展创新性抗缺氧药物提供实验依据。本研究对揭示低氧适应本质、攻克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。

综合应用生物组学、化学生物学与分子生物学、分子代谢示踪及实验药理学等多学科新技术方法，通过我们建立的斑马鱼和细胞低氧损伤与适应模型，对低氧损伤与适应的关键基因、蛋白和内源性小分子代谢产物进行系统的分析和表征。对低氧损伤和适应的内源性小分子、代谢途径和关键调控网络进行系统分析。发现了内、外源性抗缺氧活性物质及其代谢物、关键节点和代谢途径，研究探索了这些抗缺氧物质在低氧适应中的作用及分子机制，揭示了一些低氧适应的病理生理学本质。分析了与低氧适应紧密相关的重要代谢通路，如鞘脂和甘油磷脂代谢途径、氨基酸、卟啉和泛酸等代谢途径。结果为发展创新性抗缺氧药物提供了坚实的实验依据。本课题研究对揭示低氧适应的本质、攻克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。.结果已在国内外SCI收录杂志上发表5篇论文。培养出站博士后2人，毕业博士3人，硕士3人，本科生5名，科研骨干2人。目前在读博、硕研究生6名。主要工作在18届日本京都世界药理学大会上作了口头交流，在2019北京药物代谢国际学术研讨会上作了“低氧组学与分子机制”的大会报告，博士生在第12届全国药物和化学异物代谢学术会议获优秀墙报二等奖。