基质细胞中平分型GlcNAc调控黏附因子MCAM表达并重塑MDS骨髓微环境的机制研究

骨髓微环境对骨髓增生异常综合征（MDS）的发生发展异常重要，调控骨髓（微环境）基质细胞中黏附分子MCAM的表达可影响MDS克隆细胞增殖，但糖基化对MCAM表达及其功能的影响尚未有报道。预实验发现MDS病人骨髓基质细胞平分型GlcNAc显著降低；在骨髓基质细胞HS27a中过表达平分型GlcNAc导致MCAM表达下调，而在基质细胞HS5敲减平分型GlcNAc致MCAM表达上升；质谱证实MCAM存在平分型GlcNAc修饰，但平分型GlcNAc调控MCAM是否进一步影响MDS克隆细胞的增殖等还不明确。本项目提出假设：骨髓基质细胞中平分型GlcNAc可以调控MCAM表达，以此重塑骨髓微环境并介导MDS克隆细胞的增殖和凋亡等行为。项目将利用共培养体系，结合小鼠及临床样本，研究基质细胞平分型GlcNAc影响MCAM表达，重塑MDS微环境以介导MDS克隆细胞增殖等的机制，以期为MDS的诊疗提供理论依据。

Bone marrow microenvironment is essential for development of Myelodysplastic Syndromes(MDS). Modulation of MCAM, which is the typical marker of bone marrow microenvironment, in stroma cells can interfere with the proliferation of MDS clonal cells. However, if glycosylation of MCAM can regulate its expression and function still remains unclear. In our preliminary data, expression of bisecting GlcNAc is lower in patients with MDS than that in healthy controls. We further found that over-expressing bisecting GlcNAc in stroma HS27a cells results in down-regulated expression of MCAM, and inhibition of bisecting GlcNAc in stroma HS5 can lead to up-regulated expression of MCAM. Mass spectrometry results show the direct modification of the bisecting GlcNAc on MCAM. Our hypothesis is the bisecting GlcNAc caused altered expression of MCAM in stroma cells can remodel the bone marrow microenvironment and determine the cell fate of MDS clonal cells. In this proposal, we will study the mechanisms of how bisecting GlcNAc caused altered expression of MCAM in stroma cells and in turn interfere with cell proliferation and apoptosis of MDS clonal cells using comprehensive in vitro and in vivo models. The results of this proposal will lay a theoretical foundation for further research on bisecting GlcNAc in bone marrow microenviornment.