坏死性凋亡在造血干细胞辐射损伤中的作用及其机制研究

Ionizing radiation causes long-term injury of hematopoietic stem cells (HSC), however, effective therapeutic protocols to ameliorate this kind of injury have not been developed. Recent studies have found that necroptosis contributes to the hematopoiesis under both physiological and stress conditions, and reactive oxygen species (ROS) functions in a positive feedback circuit that ensures effective induction of necroptosis. In our preliminary studies, exposure of mice to total body irradiation caused a persistent increase in ROS production in HSC, associated with the inhibition of HSC’s functions. Reception interaction protein 1 (RIP1), which is an essential regulator in the initiation of necroptosis, highly expressed in bone marrow cells in radiated mice, which elevated expression was also consistent with the inhibition of HSC’s functions following irradiation. These preliminary findings suggest that necroptosis might be involved in the pathogensis of HSC injury induced by radiation. Therefore, the present project will deeply study the role of necroptosis and the underlying mechanism(s) in mediating radiation-induced HSC injury by in vitro cell models and in vivo animal models with hematopoietic injury. It is expected that these studies will provide evidence and fundation for further exploration of potential application of necroptosis as a novel target in protection and therapy of hematopoietic injury, and with important experimental contribution to the development of radioprotective agents in future.

电离辐射可导致造血干细胞(HSC)持久性损伤，且目前缺乏有效的干预手段。坏死性凋亡参与调节生理和应激状态下骨髓造血功能，活性氧(ROS)参与坏死性凋亡通路的正反馈调控。我们前期研究发现在全身辐照动物HSC的持续性的ROS水平增加与骨髓持久性抑制显正相关，且坏死性凋亡关键因子受体相互作用蛋白1(RIP1）在辐射损伤小鼠骨髓细胞显现增高，且RIP1水平改变与骨髓细胞辐射损伤程度一致，提示坏死性凋亡可能参与了调节HSC辐射损伤。本项目拟在大量预实验研究的基础上，采用体外细胞和体内动物造血系统辐射损伤模型，深入研究辐照小鼠的骨髓HSC中坏死性凋亡通路关键分子及其相应的ROS水平变化规律，以探讨坏死性凋亡在造血系统辐射损伤中所起的重要作用及其相关机制。本研究将为临床造血系统辐射损伤机制和救治提供新思路，也为坏死性凋亡作为新靶点在骨髓型辐射损伤防治药物和技术的研发提供实验依据和基础。

电离辐射可导致造血干细胞(HSC)持久性损伤，且目前缺乏有效的干预手段。坏死性凋亡参与调节生理和应激状态下骨髓造血功能。在本项目中我们的研究证实坏死性凋亡是造血干细胞辐射损伤的主要机制之一，坏死性凋亡关键因子受体相互作用蛋白1（RIP1）在辐射损伤小鼠骨髓细胞显现增高，且RIP1水平改变与骨髓细胞辐射损伤程度一致；坏死性凋亡抑制剂Nec-1能够有效提高致死剂量射线照射小鼠的生存率，Nec-1可以有效改善受照射小鼠的造血系统损伤。本项目完成了计划书中的既定目标，证明了坏死性凋亡在造血系统辐射损伤中的作用，拓宽了造血系统辐射损伤的基础研究，也为辐射损伤防护与治疗临床应用研究提供了新的思路。