新型衔接蛋白LMBRD2介导中性粒细胞功能障碍在脓毒症发生发展中的作用和机制研究

中性粒细胞功能障碍是脓毒症发生发展的关键环节，其中迁移障碍和凋亡延迟是其重要表现，但机制尚未完全阐明。趋化受体CXCR2等内化是中性粒细胞迁移障碍的重要机制，同时内化分子复合物又可激活下游信号调控凋亡。LMBRD2是一种新型受体内化衔接蛋白，我们预实验显示脓毒症患者中性粒细胞LMBRD2上调数百倍，敲减后可改善中性粒细胞迁移障碍和凋亡延迟。我们推测LMBRD2上调可能是介导脓毒症时中性粒细胞迁移障碍和凋亡延迟的重要因素。本项目拟从临床层面探讨LMBRD2与脓毒症患者中性粒细胞功能障碍及临床病情的相关性；离体层面探讨LMBRD2对脓毒症中性粒细胞迁移障碍和凋亡延迟的调控作用和分子机制；在体层面利用CKO小鼠证实中性粒细胞LMBRD2对脓毒症发生发展的影响。本项目将阐明LMBRD2介导中性粒细胞功能障碍的机制，为临床上脓毒症的干预提供新靶点，有重要的理论价值和应用前景。

Neutrophil dysfunction is one of the key processes of sepsis, as manifested by the disordered migration and delayed apoptosis, but the molecular mechanism remains unclear. Internalization of chemotactic receptor such as CXCR2 is the cause of neutrophil migration dysfunction, and the complex composed of internalized receptor and adapter β-arrestin can activate the apoptosis-related pathways such. LMBRD2 is a new potential adapter protein for complex of internalized receptors. Our preliminary study showed that LMBRD2 was upregulated for several hundred times in septic neutrophils, and the knockdown of LMBRD2 with siRNA transfection could improve the disordered migration and delayed apoptosis. Thus we speculated that LMBRD2 might be the key molecule mediating neutrophil dysfunction during sepsis. The present program was designed to investigate the correlation of LMBRD2 with neutrophil dysfunction and clinical severity in septic patients; to investigate the role and mechanism of LMBRD2 in disordered migration and delayed apoptosis of septic neutrophils; to investigate the role of neutrophil LMBRD2 in the pathogenesis of sepsis in LMBRD2 CKO mice. The final aim of this program was to clarify whether LMBRD2 was involved in neutrophil dysfunction and thereby promoting the progression of sepsis, so as to provide a new target for treating sepsis in future.