近年来大量研究显示重型再生障碍性贫血（SAA）发病与免疫异常密切相关。我们既往研究发现SAA患者NK细胞数量、功能异常，免疫监控功能不足，是导致SAA免疫功能亢进的重要因素，但导致NK细胞异常的原因尚不清楚。申请人近年来一直从事NK细胞在SAA免疫发病机制中作用的研究，蛋白质组学筛选过程中发现SAA患者NK细胞组蛋白H3水平异常，进一步验证发现H3K4甲基化水平增高，而调节H3K4甲基化水平的Ash1L明显减低。故本次课题研究在前期工作的基础上，就SAA患者Ash1L表达及其与NK细胞H3K4甲基化、疾病状态相关性进行分析；通过体外细胞模型干扰Ash1L表达水平，探索其对NK细胞H3K4甲基化水平、增殖、分化等功能的影响，分析这种改变对其他免疫细胞功能的影响；采用SAA小鼠模型验证Ash1L调控NK细胞H3K4甲基化水平对疾病发展的影响，为明确SAA的免疫发病机制及开辟新的治疗方向提供基础

A large number of studies have indicated that severe aplastic anemia (SAA) is an immune mediated disease. Our previous studies have suggested that the number and function of NK cells in SAA patients were abnormal. In addition, the inadequate immune surveillant function of NK cells was an important factor leading to the immune disorders of SAA. Yet the cause of NK cell abnormality is still unclear. My research team has been engaged in studying the role of NK cells in the pathogenesis of SAA in recent years. We indentified the level of Histone 3 of NK cells in SAA patients was abnormal with proteomic techniques. Further verification study showed that H3K4 methylation level was increased, while Ash1L which regulated H3K4 methylation was decreased significantly. Based on our previous work, our current study aims to analyze Ash1L expression in SAA patients and its correlation with H3K4 methylation of NK cells and the disease severity. By interfering with Ash1L expression in vitro, we intend to explore the effects of Ash1L on H3K4 methylation level, proliferation and differentiation of NK cells, and their further influence on other immune cells. The SAA mouse model will be used to verify the effects of Ash1L on the disease development. We hope to provide a basis for revealing the immunopathogenesis of SAA and opening up new therapeutic directions.