抗氧化小分子化合物扩增人造血干细胞及其放射保护作用的研究

目前脐带血中造血干细胞（HSCs）数量不够、质量欠佳造成移植成功率低等诸多瓶颈极大地限制了脐带血HSCs的应用。在前期工作中我们将三维结构模建、计算机虚拟筛选、人HSCs功能实验等多个环节有机联结起来，建立了以单细胞技术为特点与HSCs相关的药物设计、筛选及药效研究平台，并利用此平台筛选到可扩增小鼠及人HSCs的多个活性小分子化合物。结合已有研究基础，本课题拟从抗氧化小分子化合物入手，对已筛选到的先导化合物进行进一步深入研究，通过一系列体内外实验明确其扩增人HSCs及放射保护的作用，阐释作用通路及关键靶点。在此基础上对阳性化合物的结构进行优化，评价其安全性并与作用于不同信号通路及靶点的已知化合物联用。以期能获得兼具扩增HSCs数量同时提高HSCs质量的优选方案，为改善临床患者脐带血HSCs的植活成功率提供新方法、新技术。

The use of umbilical cord blood transplantation (UCBT) has been substantially limited by the finite number of hematopoietic stem and progenitor cells (HSPCs) in a single UCB unit. Small molecules that not only quantitatively but qualitatively stimulate ex vivo HSPCs expansion should facilitate the clinical use of HSCs transplantation and gene therapy. We have described a novel ex vivo human HSCs assay that combines single-cell sorting and high-throughput flow analysis techniques to investigate the self-renewal and colony-forming capabilities of HSCs and further screen HSC-related small-molecule compounds. Based on the primary screening of an antioxidant library, we identified lead compounds which were able to expand functional HSCs in a short-term culture. In this project, the lead compounds for regulation of human HSCs will be explored. We will also design and screen new compounds for human HSCs expansions and radiological protection. Development of more effective functional compounds or its combinations with other HSCs expansion agents may offer effective agents for HSCs expansion in the future.