干细胞在组织再生及对抗衰老中具有巨大的应用前景，然而，对病理或衰老状态下干细胞功能的调控机理缺乏深入了解，限制了干细胞的临床应用。最新研究发现人类造血干细胞（HSC）对药物诱导的内质网应激非常敏感，但是其具体机制还不清楚。DDRGK1作为新发现的内质网蛋白，在内质网应激反应发生时，能够保护细胞免于凋亡。我们前期数据表明小鼠HSC对内质网应激诱导的细胞凋亡非常敏感，基因沉默DDRGK1能够诱导内质网应激反应，显著降低了小鼠HSC的造血重建能力。为进一步研究DDRGK1在HSC功能及衰老中的作用，我们通过CRISPR-Cas9介导的基因组靶向修饰技术构建了DDRGK1条件敲除小鼠。通过建立造血系统特异的DDRGK1敲除小鼠，以及DDRGK1和CHOP双基因敲除小鼠，阐明HSC应对内质网应激的分子机制，为推进干细胞衰老研究及其在临床的应用提供理论和实验依据。

Stem cell have shown enormous potential in the area of tissue regeneration and anti-aging. However, lack of understanding for the mechanism of stem cell function regulation under pathological or aging state , which limit the clinical application of stem cell. The latest study found that human hematopoietic stem cell (HSC) is very sensitive to drug-induced endoplasmic reticulum stress (ER stress), but the exact mechanism is unclear. DDRGK1, as a newly found endoplasmic reticulum protein, can protect cell from apoptosis when the ER stress response occurs. Our preliminary data suggest that mice HSC is very sensitive to ER stress induced apoptosis. Meanwhile, knocking down DDRGK1 can induce ER stress response, and significantly decrease mice HSC hematopoietic reconstitution capacity. To further investigate the role of DDRGK1 in HSC function and senescence，We generated a DDRGK1 conditional knockout (KO) mice by CRISPR-Cas9 mediated genome modification technology. Through generating the hematopoietic system-specific DDRGK1 KO mice , as well as DDRGK1 and CHOP double KO mice , to elucidate the molecular mechanism of endoplasmic reticulum stress response in the HSC, which will promote stem cell aging research and provide theoretical and experimental basis to clinical application.