生命早期低水平铅暴露诱导造血干细胞衰老的机制及干预研究

Heavy metal pollution is a global environmental problem. Lead (Pb) is of particular concern due to the long-lasting and possibly irreversible nature of effects for children.The levels of lead contamination of the environment have decreased in recent decades in China, but the low level exposure of lead is exist and affect everybody, especially the individual in early life. Most previous studies have focused on neurotoxicity of lead. Our previous studies found that low level of lead exposure induced obvious toxic effects of hemopoietic system. The senescence phenotype of hematopoietic stem cells was observed with unclear mechanisms. In this proposed research project, two kinds of hematopoietic stem cells (derived from embryo and bone marrow) were used as study object. This study systematically investigates the effect and its mechanisms of pyruvate kinase M2 (PKM2) on the HSC senescence. Based on the previous natural drug monomer screening results, allicin and Rg1 were used to investigate the antagonistic effects of low level lead exposure induced HSC senescence in mouse model of low level lead exposure in early life for elaborating the mechanism(s) of low level lead exposure induced HSC senescence and intervention strategies.

重金属污染是世界范围内环境问题，铅污染危害最重，铅暴露对生长发育期儿童的不可逆损伤是医学领域重大前沿问题。近年我国儿童血铅水平明显下降，但低水平暴露持续存在，几乎每人都不同程度地暴露于铅环境，铅对生命早期个体毒性更甚，既往研究多在其神经毒性。我们前期研究示:低水平铅暴露对造血系统损害依然显著，主要表现为诱导造血干细胞（HSC）衰老，其机制未知，本项目以此为切入点，以胚胎HSC和骨髓HSC及生命早期铅暴露个体为体外和体内研究对象，探讨在铅氧化应激损伤过程起关键调节作用的M2型丙酮酸激酶（PKM2）对HSC衰老的影响及机制,并以生命早期低水平铅暴露小鼠为药物干预模型，结合前期天然药物单体筛选结果，探讨Allicin和人参皂苷Rg1在拮抗低水平铅暴露诱导HSC衰老中的作用，以期阐述低水平铅暴露诱导HSC衰老的机制及干预策略，旨在为低水平铅暴露造血系统损伤的治疗和预防提供新的理论依据和干预靶点。

重金属污染是世界范围内的公共卫生问题，重金属污染持续存在，其中铅污染危害最重，铅暴露对生长发育期儿童的不可逆损伤是医学领域的重大前沿问题。近年我国儿童血铅水平明显下降，但低水平暴露持续存在，几乎每人都不同程度地暴露于铅环境，铅对生命早期个体毒性更甚，既往研究多在其神经毒性。我们前期研究显示，低水平铅暴露对造血系统损害依然显著，主要表现为诱导造血干细胞（HSC）衰老，但是其机制未明，本项目以此为切入点，以胚胎HSC和骨髓HSC及生命早期铅暴露个体为体外和体内研究对象，发现在铅氧化应激损伤过程起关键调节作用的M2型丙酮酸激酶（PKM2）在HSC衰老中的调节作用。以生命早期低水平铅暴露小鼠为药物干预模型，结合前期天然药物单体筛选结果，发现Allicin和人参皂苷Rg1在拮抗低水平铅暴露诱导HSC衰老中的作用，初步阐释了低水平铅暴露诱导HSC衰老的机制及干预策略，为低水平铅暴露造血系统损伤的治疗和预防提供了新的理论依据和干预靶点。