RBPJ基因突变通过p38MAPK促进克隆增殖在阵发性睡眠性血红蛋白尿症发病中的作用研究

阵发性睡眠性血红蛋白尿症（PNH）发病与PIG-A基因突变之外的二次基因突变密切相关。申请人前期通过基因组全外显子测序发现部分PNH患者存在RBPJ基因的高频突变且与PNH异常克隆增殖密切相关，但其分子机制尚不明确。本课题拟在前期研究基础上，以PNH患者及PNH小鼠模型为研究对象，对RBPJ基因突变促进PNH克隆增殖的分子机制进行深入探索：①分析PNH患者及PNH小鼠模型中RBPJ基因表达及其与PNH疾病状态之间的相关性；②探索RBPJ基因通过调控 MAPK信号通路促进PNH克隆增殖的分子机制；③构建RBPJ突变位点克隆，应用X射线晶体衍射及核磁共振对目的蛋白结构及生物学功能进行分析；④动物模型检测RBPJ基因调控 MAPK信号通路的生物学特性。本研究将有助于寻找PNH治疗新的靶点。

The pathogenesis of paroxysmal nocturnal hemoglobinuria (PNH) is closely related to additional gene mutations besides PIG-A gene mutations. Previous studies showed that most of the PNH patients had high frequency mutation of RBPJ gene through the whole genome exon sequencing, which played an important role in the pathogenesis of PNH, but its molecular mechanism is still unclear. On the basis of previous research work, the molecular mechanism of RBPJ gene mutation promoting PNH cloning proliferation was explored in detail by taking PNH patients and PNH mice model as research objects. The following aspects were analyzed: ① Analyze the expression of RBPJ gene in PNH patients and its correlation with PNH disease status; ② Explore the molecular mechanism of RBPJ gene promoting PNH cloning and proliferation by regulating the MAPK signaling pathway;③ Construct the clone of RBPJ mutation site, analysis of the structure and biological function of the target protein by X-ray crystallography and nuclear magnetic resonance ; ④ Detect the biological characteristics of RBPJ gene regulating the MAPK signaling pathway in animal models. This study will be helpful to find new targets for PNH treatment.