电离辐射致骨髓造血慢性损伤的效应与机制研究

骨髓造血组织是电离辐射敏感组织，但电离辐射对骨髓造血的远期影响作用与机制尚远未阐明。基于骨髓造血干细胞（HSCs）自身特性及我们前期发现，推测辐照后HSCs基因组不稳定性的延迟形成及子代细胞遗传累积引发了系列病理反应，从而引起HSCs及骨髓造血慢性损伤。本项目拟采用基因组及转录组测序、代谢组学分析、单细胞移植等技术，首先构建辐照小鼠HSCs基因组不稳定性发生图谱并筛选易感基因，再从微核延迟形成与子代细胞遗传累积、cGAS-STING通路活化、局部炎症反应、能量代谢模式改变并最终通过氧化应激和表观遗传重塑影响HSCs自我更新和偏向分化等层面，深入阐明辐射诱导骨髓造血慢性损伤的分子机制。同时，结合HSCs动员与再定植特性揭示局部辐照引起远端骨髓造血损伤的发生机制。最后，观察调控cGAS-STING通路、炎症反应和线粒体代谢对HSCs慢性损伤的防治作用，为电离辐射后远期造血损伤的救治探寻新思路。

Although it is well-defined that bone marrow (BM) is sensitive to ionizing radiation (IR), the long-term BM hematopoietic damages induced by IR and the underlying mechanisms are still far from elucidated. Based on the unique features of hematopoietic stem cells (HSCs) and our previous research findings, we presume that delayed and accumulated formation of progeny-hereditary genomic instabilities of HSCs after IR exposure triggers a series of pathological reactions, resulting in long-term HSC damages and ultimately leading to abnormal BM hematopoiesis. In this study, by adopting genome and transcriptome sequencing, metabolomics analysis and single cell transplantation, we will firstly construct the map of genomic instabilities in HSCs and screen the susceptibility genes. Then, we will deeply elucidate the molecular mechanisms of IR-induced long-term HSC damages including declined self-renewal, myeloid-biased differentiation from the perspectives of delayed formation and progeny-hereditary accumulation of micronuclei, cGAS-STING pathway activation, local inflammatory response, energy metabolism pattern shift, ROS overproduction and epigenetic reprogramming. Subsequently, we will reveal the mechanisms of abscopal BM hematopoietic damages induced by IR from the perspectives of HSC mobilization and recolonization. Finally, we will evaluate the preventive and therapeutic effects of intervention of cGAS-STING pathway, inflammatory response and mitochondrial metabolism on IR-induced long-term HSC damages. The aim of this study is to unmask the effect and underlying mechanisms of IR in inducing HSC long-term damage and to search effective approaches for the treatment of IR-induced long-term hematopoietic damage.