MFHAS1在脓毒症器官损伤期单核细胞分化与功能失调中的作用与机制研究

脓毒症患者器官损伤期单核细胞向树突状细胞（DC）分化减少，而巨噬细胞分化增加及DC功能障碍的调控机制未明，是制约临床诊疗的关键瓶颈之一。我们前期研究发现脓毒症患者外周血单核细胞中Wnt5a和恶性纤维性组织细胞瘤扩增序列1（MFHAS1）表达显著高于非脓毒症患者，且重组Wnt5a和MFHAS1蛋白能增强DC活化T细胞的能力，而沉默MFHAS1使得DC中Dectin-1通路下游蛋白表达增加进而抑制炎性反应。基于此，我们假设MFHAS1参与调控Wnt/Dectin-1信号通路，继而引起单核细胞向DC分化及功能演变。本研究充分利用mfhas1基因沉默斑马鱼和Mfhas1基因敲除小鼠，从细胞、分子和整体动物多维度研究MFHAS1通过调控Wnt/Dectin-1信号通路影响单核细胞向DC分化及其功能的确切机制，为阻遏和靶向治疗脓毒症患者过度炎性反应造成的器官功能损伤提供科学依据。

Diminished monocyte to dendritic cell (DC) differentiation, and macrophage predominance, has been shown to correlate with adverse clinical outcomes such as organ dysfunction in sepsis. It is one of the several bottlenecks restricting clinical treatment of sepsis. None studies in above field are reported. We found that the expressions of MFHAS1 (Malignant fibrous histiocytoma amplified sequence 1) and Wnt5a in peripheral blood mononuclear cell of septic patients were significantly higher than healthy controls. We also found that recombinant Wnt5a and MFHAS1 could enhance the ability of DC to activate T cells, indicating that MFHAS1 might be involved in monocyte differentiation. Mechanistically, we found that MFHAS1 knockdown increased the protein expression of Dectin-1 downstream signaling pathway, alleviating inflammation. Hence, we assumed that MFHAS1 could regulate monocyte differentiation to DC and its function, through regulating Wnt/Dectin-1 signaling. Our project aimed to investigate the role of MFHAS1 in regulating monocyte differentiation and DC function, also to reveal the underlying mechanism in the regulation of Wnt/Dectin-1 signaling, from multi-dimensions of cells, molecules and whole animals, making the best use of mfhas1 knockdown zebrafish and Mfhas1 knock-out mouse. The goal of our project is to establish the foundation for the repression and target treatment of the excessive inflammatory response in the stage of organ dysfunction in septic patients.