反转录转座子LINE-1 在造血干细胞衰老中的作用及机制

Hematopoietic stem cells senescence is one of the sources of hematopoiesis aging. Aging HSC is often accompanied with genomic instability, DNA damage response, heterochromatin loss and other characteristics. And these features are related to the activation of the retrotransposon LINE1, while the activation of LINE1 may also promote the aging of HSC. This project will examine the role and mechanism of retrotransposon LINE1 in normal aging and replicative aging models of hematopoietic stem cells, explore its potential as a novel target for clinical treatment of aging-related diseases. Our previous data showed that the activation of retrotransposon LINE1 caused by SIRT6 deletion accelerated the aging of mouse HSC and blood system, but it is still necessary to use a variety of animal models to further study the activation and the regulation of LINE1 in the HSC aging, and the use of drugs and genetic models to study the inhibition of LINE1 on normal aging and replication of aging. In this study, we mainly based on tissue-specific knockout and knock-down mouse, reveal the mechanism of LINE1 in the HSC aging, and explore the strategy of targeting LINE1 as the target, so as to control the organ senescence and its related diseases research to open up a new perspective.

血液系统衰老的因素之一是造血干细胞（HSC）衰老。衰老的HSC常伴随基因组不稳定性、DNA损伤反应，异染色质丢失等特征。而这些特征是与反转录转座子LINE1的激活相关的。因此本项目将研究LINE1的激活在HSC衰老中的作用及机理，并探讨其作为血液衰老相关疾病临床治疗新型靶点的可能性。我们前期数据表明SIRT6缺失背景下LINE1的激活会加速HSC和血液系统的衰老并缩短小鼠的寿命；另外，端粒敲除HSC中LINE1也被激活，是否LINE1的激活参与了端粒敲除这种复制性衰老的过程将有待研究。本课题将利用LINE-1元件ORF1p及ORF2p敲减小鼠模型，端粒敲除小鼠模型及老龄SIRT6造血系统特异性敲除小鼠模型等研究LINE1被激活的机制及其促进HSC衰老的机制，并将利用药物手段研究抑制LINE1对HSC衰老的影响。本研究将深入揭示LINE1在HSC衰老中的作用机制，为器官衰老的研究开拓新视角。

血液系统衰老的因素之一是造血干细胞（HSC）衰老。目前我国人口老龄化与经济发展仍面临诸多挑战，而医药问题更是当前社会聚焦的热点。新药研发伴随着高投入、长周期、高风险，而探索已开发药物的新用途不但可以节约大量的临床试验、上市审批时间，更可以为减少医疗支出，缓解社会压力做出巨大贡献。本项目利用条件性敲除技术、干细胞移植技术等首次将反转录转座子LINE1、造血干细胞、衰老三者有机结合起来，证明了LINE1的被激活是诱发造血干细胞及血液系统衰老症状的重要因素，并揭示了LINE1激活cGAS炎症反应通路在造血干细胞衰老中存在的新功能，同时本项目也探索了FDA批准的核苷类抑制剂药物3TC的新应用方向，以上研究成果已发表在2020年的Signal Transduction and Targeted Therapy杂志。项目负责人在本项目的培养期内获得了国自然优青项目的资助。本项目的成果将为衰老过程中细胞功能变化以及衰老相关血液疾病的诱发机制提供重要参考，并为中老年血液疾病的防治提供新的突破点和新的药物参考。