阵发性睡眠性血红蛋白尿症（PNH）发病与除PIG-A基因突变之外的二次基因突变密切相关。申请人前期研究通过PNH患者全基因组外显子测序方法，发现部分PNH患者存在CUX1基因的高频突变。CUX1基因突变可能影响Beclin1基因致自噬水平降低，从而促进PNH克隆增殖，在PNH发病中发挥重要作用。但目前其调控自噬的机制尚不明确。本课题拟在前期研究工作基础上，以PNH患者及PNH小鼠模型为研究对象，对CUX1基因通过调控自噬促使PNH克隆获得增殖优势机制进行深入探索：①分析PNH患者及PNH小鼠模型中CUX1在PNH中的表达及其与自噬、PNH疾病状态相关性；②探索CUX1调节细胞自噬的下游信号通路；构建CUX1高表达PNH克隆，通过基因芯片方法探寻其调控自噬的分子机制；③动物模型检测CUX1基因调控自噬的生物学特性。本研究将有助于深入探索PNH发病机制，为该疾病寻找新的治疗靶点奠定实验基础。

The pathogenesis of paroxysmal nocturnal hemoglobinuria (PNH) is closely related to second gene mutation besides PIG-A mutation. In previous work, the applicant found that PNH patients have a variety of mutations in addition to PIG-A mutation, among which the CUX1 gene is believed to decrease the autophagy through affecting Beclin1 gene, promote the proliferation of PNH cells, and may play an important role in the pathogenesis of PNH. Based on previous work, we intend to use PNH patients and PNH mice model as the research objects to explore in-depth the CUX1 gene in regulating autophagy-therefore regulating PNH proliferation. Our research contents are as follows: ① Analysing the expression of CUX1 and its correlation with autophagy and PNH disease status; ② Exploring the signalling pathway of CUX1 gene, and the molecular mechanism of autophagy regulation and PNH proliferation by CUX1 gene through gene microarray in CUX1 overexpression clone, and revealing the effect of CUX1 gene expression on the severity of PNH and the clonal proliferation of PNH; ③ Using animal models to detect the biological characteristics of CUX1 gene in regulating autophagy. This research will be helpful to further explore the pathogenesis of PNH, and will lay an experimental base to find a new therapeutic target for PNH.