长期骨髓抑制是放射暴露最主要的远期损伤，尚无有效治疗手段。研究表明，造血微环境损伤是放射致长期骨髓抑制的主要原因之一，但机制未明。我们研究发现，AML患者骨髓细胞低表达CRIF1，6Gy照射后BM-MSCs衰老率显著高于健康供者组；CRIF1可与CDK2相互作用；放射后BM-MSCs表达CRIF1升高、P21与CDK2的结合降低、CDK2活性残留、衰老减低，而抑制CRIF1表达则可增加P21与CDK2的结合、CDK2失活、衰老增加。据此推测：放射后CRIF1表达升高，与P21竞争结合CDK2促进CDK2活性残留，从而抑制BM-MSCs衰老进程。本项目拟明确CRIF1、P21与CDK2的作用关系和位点，解析CRIF1调节CDK2活性在放射致BM-MSCs衰老中的分子机制，体内实验探索P21/CDK2界面抑制剂救治长期骨髓抑制的可行性。为阐明放射致长期骨髓抑制的发生机制和药物研发奠定基础。

Long-term myelosuppression is the most important long lasting and latent injury induced by radiation exposure, and there is no effective treatment to ameliorate the injury. Hematopoietic microenvironment damage is one of the main causes of radiation-induced long-term myelosuppression. However, the mechanisms by which radiation induces hematopoietic microenvironment damage have not been clearly defined. Our study found that the bone marrow cells of AML patients had a low expression of CRIF1, and the BM-MSCs senescence rate was significantly higher than that of healthy donors after 6 Gy irradiation; CRIF1 could interact with CDK2; expression of CRIF1 increased after irradiation, which caused the decrease in the binding of P21 to CDK2, reservation of residual activity of CDK2 and reduced senescence; while inhibition of CRIF1 expression resulted the increase in the binding of P21 to CDK2, CDK2 inactivation, and increased senescence. It is speculated that the increased expression of CRIF1 could compete with P21 binding to CDK2 which promotes the reservation of residual activity of CDK2, thereby inhibits the senescence process of BM-MSCs. This project aims to clarify the role and interaction sites of CRIF1, P21 and CDK2, and analyze the molecular mechanism of CRIF1 regulating CDK2 activity in the senescence of BM-MSCs induced by radiation, and explore the feasibility of P21/CDK2 interfacial inhibitor for long-term myelosuppression in vivo. This study can shed light on the elucidation of the mechanism of radiation-induced long-term myelosuppression and drug development.