激活外源性细胞凋亡清除老化造血干细胞在辐射导致的慢性损伤骨髓重建中的作用

电离辐射导致的急性辐射综合征已有防治措施，但其引起的慢性延迟效应没有应对手段。我们证明了辐射导致造血干细胞(HSC)老化在慢性骨髓衰竭中起重要作用，辐射后髓内老化HSCs与存留正常HSCs共存，ABT263通过清除部分老化细胞改善慢性HSC损伤。由此提出假说：清除辐射产生的老化HSCs或激活髓内存留正常HSCs，可改善辐射导致的慢性骨髓损伤及促进造血功能重建。我们将抑制FLIP-L表达或应用Fas抗体激活外源性细胞凋亡、ABT263激活内源性细胞凋亡清除辐射后髓内老化HSCs，恢复正常HSC功能；通过Poly(I:C) 和Plerixafor激活及移位辐射后髓内存留正常HSCs，重建骨髓正常功能；通过体外单个HSC克隆形成、体内单个HSC骨髓重建和RNA-Seq分析HSC重建前后与正常HSC的分子特征。将证实以老化HSCs和存留正常HSCs为靶标能成为新的抗辐射骨髓慢性延迟效应的措施。

Although the prevention and treatment of acute radiation syndrome caused by ionizing radiation have been extensively studied, the chronic delayed effects caused by ionizing radiation, such as chronic bone marrow failure, remain elusive. Our previous studies demonstrate that radiation-induced hematopoietic stem cells (HSCs) senescence plays a crucial role in chronic bone marrow failure. Furthermore, ABT263 ameliorates radiation-induced chronic HSC injury by eliminating senescent HSCs, and the senescent HSCs coexist with the residual normal HSCs in bone marrow after total body irradiation. The hypothesis of this project is that eliminating radiation-induced senescent HSCs or activating residual normal HSCs in bone marrow post irradiation can attenuate chronic bone marrow injury and promote hematopoietic system functional reconstitution. To test this hypothesis, we will eliminate the senescent HSCs in bone marrow after irradiation by Fas antibody or inhibiting FLIP-L expression to activate extrinsic apoptotic pathway, ABT263 to activate intrinsic apoptotic pathway, and restore the normal HSC reconstitution function in bone marrow after irradiation. The functional and molecular characteristics of HSCs before and after irradiation were analyzed by in vitro single HSC cloning formation, in vivo single HSC bone marrow reconstitution and HSC RNA-Seq. Targeting senescent HSCs and residual normal HSCs may be a new avenue to prevent irradiation-induced bone marrow chronic delayed effects.