Erstellen einer Knockout Maus als Modell für die X-gekoppelte lymphoproliferative Erkrankung und Analyse des SH2D1A Gens auf eine mögliche Tumorsuppressorfunktion an Non-Hodkin-Burkitt Tumor Zellinien

SH 2D 1A基因在约70%的X连锁淋巴增生性疾病（XLP）患者中以及在具有早发性非霍奇金伯基特淋巴瘤（NHBL）的EB病毒（EBV）阴性患者中突变。SH 2 D1 A编码SH 2结构域蛋白，其抑制调节B细胞和T细胞增殖和分化的信号级联的激活。在早发NHBL患者中发生SH 2D 1A突变，与EBV感染无关，提示SH 2D 1A基因具有肿瘤抑制功能。我将创建一个SH 2D 1A-null小鼠作为XLP的模型，并研究SH 2D 1A的下游信号传导。为了研究该基因在肿瘤增殖方面的功能特性，将建立来自XLP患者的NHBL细胞系并用SH 2D 1A转染。提出了在NHBL系BJAB、CA 46和MC 116中过表达被SH 2D 1A抑制的蛋白，以分析这些蛋白是否参与具有染色体1 q23 -25重复的NHBL的高度恶性。

The SH2D1A gene is mutated in about 70 % of X-linked lymphoproliferative disease (XLP) patients and also in Epstein-Barr Virus (EBV) negative patients with early onset non-Hodgkin Burkitt lymphoma (NHBL). SH2D1A codes for an SH2-domain protein, which inhibits the activation of a signalling cascade regulating proliferation and differentiation of B- and T-cells. The occurrence of SH2D1A mutations in patients with early onset NHBL, independent of EBV infection, suggests a tumor suppressor function for the SH2D1A gene. I will create an SH2D1A-null mouse to serve as a model for XLP and to study the downstream signalling from SH2D1A. To investigate the functional properties of this gene in terms of tumor propagation a NHBL cell line from an XLP patient will be established and transfected with SH2D1A. Overexpression of proteins inhibited by SH2D1A in NHBL lines BJAB, CA46 and MC116 is proposed, to analyse if these proteins are involved in the high malignancy of NHBLs with a duplication of chromosome 1q23-25.