基于nanoLC-MS的新型精准代谢组学开发与造血干细胞衰老的代谢重塑研究

代谢组学是代谢研究的重要技术支撑，但其灵敏度低、覆盖度窄、精准度差等瓶颈仍严重制约诸多领域的代谢研究，亟需解决。申请人团队长期从事代谢组学技术研发，曾建立高灵敏技术用于微量造血干细胞（HSCs）分析，并发现HSC衰老发生脂质代谢的显著变化。基于此，前期初步建立但尚未优化的nanoLC-MS方法即已实现比常规LC-MS更高的灵敏度。本项目拟基于nanoLC-MS平台，进一步发展精准的靶向、非靶向代谢组学技术；及可同时标记多种代谢物基团的新型衍生化试剂；由此发展一系列超灵敏、宽覆盖、可定量的精准代谢组学技术，并对其进行全面的方法学考察。最后，为验证其生物研究应用潜力，拟以该系列技术对HSC衰老的代谢特征进行全面分析，揭示其代谢重塑规律，并阐释其功能。本项目中的新技术发展将为各领域代谢研究提供重要技术支撑；HSC衰老的代谢重塑研究可为延缓衰老及防治相关疾病提供新思路，具有重要科学意义和转化价值。

Metabolomics is an important technical tool for metabolic research, but there are still challenges such as low sensitivity, narrow coverage, and inability to quantify absolutely, which limits its application in metabolic research in many fields. The applicant has extensive experience in the development of metabolomics technology, and has established a high-sensitivity method for the analysis of trace HSC samples, which revealed that lipid metabolism in aging HSCs is significantly disturbed. Our preliminary study shows that nanoLC-MS can achieve higher sensitivity than conventional LC-MS. Based on the nanoLC-MS platform, this proposal aims to continue developing ultra-sensitive metabolomics technologies in three steps: targeted and non-targeted metabolomics technologies as well as new derivatization reagents that can simultaneously label multiple chemical groups. The ultimate goal is to develop an ultra-sensitive, wide coverage, and quantitative metabolomics analysis technology. Comprehensive methodological validation will also be applied. Finally, as one of the applications, we will use these technologies to analyze the metabolic characteristics of aging HSCs and reveal their metabolic reprogramming phenotype and function. This technology to be developed in this proposal will provide a strong technical support for the metabolic research in many fields; and our study on HSC aging will provide new insight into the aging associated diseases.