由N-乙酰氨基葡萄糖转移酶-III（MGAT3）催化的平分型N-糖链在骨髓造血微环境中的功能研究

骨髓造血微环境的异常能导致造血功能的紊乱，但其机制仍不明确。人骨髓基质细胞HS5和HS27a与骨髓增生异常综合征（MDS）细胞的共培养模型，常被用于研究MDS中骨髓造血微环境对造血干细胞增殖、分化及凋亡的影响。申请人前期工作发现HS27a比HS5显著促进MDS细胞在小鼠体内的增殖，预实验发现催化平分型N-糖链的MGAT3在HS5细胞中的表达显著高于HS27a。平分型N-糖链能够抑制肿瘤细胞的增殖和迁移，但在骨髓造血微环境中的功能仍未知。以此，本项目提出假设：基质细胞中由MGAT3催化的平分型N-糖链对MDS细胞增殖状态有着重要的影响。本项目通过研究MGAT3催化的平分型N-糖链对MDS细胞增殖的影响，探索MGAT3基因表达调控的分子机理，以及MGAT3和平分型N-糖链表达与MDS发展程度的相关性，以理解平分型N-糖链在骨髓造血微环境中的作用，并为MDS的临床诊断和治疗提供科学依据。

The contribution of hematopoietic bone marrow microenvironment (HBMM) to hematopoiesis is far beyond our understanding. Two stromal cells derived from healthy donor (HS5 and HS27a) co-cultured with Myelodysplastic syndrome (MDS) cells are commonly used for investigation of the crosstalk between HBMM and hematopoietic stem cells during the development of MDS. Our data have shown HS27a, but not HS5, is able to facilitate proliferation of clonal cells from patients with MDS in NSG mice when those cells are co-administrated. Our preliminary data suggested that the expression of MGAT3 gene，which encodes N-acetylglucosaminyl-transferase III (MGAT3) and its product can catalyzes the synthesis of bisecting N-glycan which is involved in inhibition of tumor proliferation and metastasis, is significantly higher in HS5 than in HS27a. Our hypothesis is the bisecting N-glycan that catalyzed by MGAT3 plays an important role in interfering with the proliferation of MDS cells. Thus, we will knockdown or overexpress MGAT3 gene in those two stromal cells and co-cultured the modified cells with MDS cell lines to explore the biological function of bisecting N-glycan in regulating proliferation in MDS cells. The present proposal is aimed at obtaining additional knowledge to define the role of bisecting N-glycan in HBMM at a basic level, and to make a contribution of clinical diagnose and treatment for patients with MDS.