白藜芦醇多聚体Vam3和Vam4对造血干细胞辐射损伤防护作用研究

Hematopoietic system damage is one of the common side effects of conventional cancer therapy using ionizing radiation (IR) and chemotherapy and the primary cause of death after accidental exposure to a high dose of total body irradiation. Moreover, an effective treatment to ameliorate the injury has not been developed yet. Several studies have shown that IR induces long-term BM injury primarily via induction of HSC senescence. A persistent increase in reactive oxygen species(ROS) and the active p38MAPK pathway contribute mainly in HSC senescence. Our previous works show that Vam3 (Amurensis H), a dimeric derivative of resveratrol, and Vam4(Heyneanol A),a tetramer derivative of resveratrol , could ameliorate radiation-induced HSC injury by down-regulated the level of ROS, and increase the ability of HSC self-renewal and reconstitution in vivo and in vitro. The protective effect of Vam3 and Vam4 was better than resveratrol which suggest that they are more effective drugs than resveratrol.Our present research aims to study the effects of Vam3 and Vam4 on irradiation-induced HSC injury by a series of experiments in vivo and in vitro. At the same time, we will also want to explore the unknown mechanisms on DNA damage,resource of ROS,metabolic pathway,and HSC senescence involved in the irradiation-induced HSC damage.This work will explore the less toxic,more effective,and more rapid onset radiation protectants, it will be of great importance in research of radiation protection.

电离辐射引起的造血系统损伤是辐射损伤的主要表现之一，也是临床肿瘤病人放疗化疗的主要并发症，目前缺乏有效的治疗方法。电离辐射引发的骨髓持久性损伤主要是由于辐射暴露后造血干细胞内持续升高的活性氧激活下游p38MAPK信号通路最终引起HSC衰老所致。我们前期预实验证实，白藜芦醇二聚体Vam3和四聚体Vam4能够降低辐射暴露后造血干细胞内活性氧水平，提高造血干细胞体外成克隆能力和体内移植重建能力，有效减轻辐射引起的造血干祖细胞损伤，效果优越于白藜芦醇，提示白藜芦醇多聚体可能为更好的辐射防护剂。本项研究以氨磷汀和白藜芦醇为阳性对照药，通过细胞学和整体实验手段探讨Vam3及Vam4优于白藜芦醇的造血系统辐射防护作用，并深入研究其在DNA损伤、ROS来源、代谢通路及辐射诱导衰老方面的防护作用机制。本项目研究能够开发出毒性更低，发挥作用更快，更加有效的辐射防护剂，对于辐射损伤防护研究具有重要意义。

电离辐射引起的造血系统损伤是辐射损伤的主要表现之一，也是临床肿瘤病人放疗化疗的主要并发症，目前缺乏有效的治疗方法。本项目通过细胞学和整体实验手段探讨Vam3对造血系统辐射防护作用，并深入研究其在DNA损伤、ROS来源、代谢通路及辐射诱导衰老方面的防护作用机制。研究显示，Vam能够减轻电离辐射引起的造血系统损伤，减轻造血干细胞自我更新及定向分化能力的辐射损伤，降低细胞内的活性氧水平。我们进一步探索Vam3的辐射损伤防护机制发现，Vam3能够降低细胞内Sirt1，Gpx1,Sod2等氧化基因的表达，上调Nrf2及其下游的抗氧化基因表达发挥抗氧化作用。我们进一步利用Nrf2基因敲除小鼠进行研究，发现Vam3能够降低受照射后Nrf2敲除小鼠细胞内的ROS，但是不能增加其细胞活力，提示Vam3通过部分调控Nrf2信号通路发挥辐射损伤防护作用。本研究提示，Vam3作为辐射损伤防护剂有良好的应用前景，值得深入开发。