细胞外基质分子介导的工程化人肝类器官构建及其在药物安全性评价中的应用

肝脏的生物安全性是决定新药研发成败的第一要素，采用合理、有效的模型预测药物-药物相互作用及潜在药物性肝损伤(drug induced liver injury, DILI)是制药领域面临的严峻科学挑战。本项目将整合组织工程学、基质组学、干细胞生物学、药物代谢动力学与毒理学等学科的新理论，系统集成多项关键技术，以不同年龄阶段的脱细胞肝脏生物支架为研究对象，通过基质组学技术系统全面分析细胞外基质(extracellular matrix, ECM)组分构成，寻找能够促进肝细胞发育成熟、药物代谢功能提升的特定ECM分子或分子组合，并将其应用于优化以人胚胎干细胞为起始细胞的肝类器官构建方案中，以期获得具有更好生物学功能的工程化人肝类器官，并将其作为药物研发早期安全性预测模型，开展药物代谢、药物-药物相互作用、创新药物毒理学研究，为突破传统的新药安全性评价模式提供新思路和有益借鉴。

The biosafety of liver is the first factor to determine the success or failure of new drug research and development. It is a serious scientific challenge to use a reasonable and effective model to predict drug-drug interaction and potential drug induced liver injury (DILI) in the pharmaceutical field. This project will be based on the research focus of "construction of safety prediction model for new drug research and development", integrate the new theories of stem cell biology, tissue engineering, pharmacokinetics and toxicology, stroma and other disciplines, systematically integrate these advanced technologies, take the acellular liver scaffolds from the rats at different ages as the research object, and comprehensively analyze them through matrisome technology, and look for specific ECM molecules or molecular combinations that can promote the development and maturity of hepatocytes and improve the drug metabolism. In order to obtain the engineered human liver organoids with better biological function, we will optimize the construction scheme of liver organoids from human embryonic stem cells by adding these ECM molecules. The developed liver organoids could be used as the early safety prediction model of drug research and development. This project will break through the traditional model of safety evaluation of new drugs. The implementation of this project is of great theoretical and practical value for improving the level of clinical safe drug use and the success rate of new drug development.