P-选择素糖蛋白配体1（PSGL-1）介导中性粒细胞募集在新生儿脓毒症中的作用及机制研究

项目名称： P-选择素糖蛋白配体1（PSGL-1）介导中性粒细胞募集在新生儿脓毒症中的作用及机制研究

项目编号： No.81501703

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 周慧婷

作者单位： 苏州大学

项目金额： 18万元

中文摘要： 由于新生儿赖以抵抗微生物感染的固有免疫反应存在缺陷,导致新生儿病患对感染引起的脓毒症易感性升高。我们前期研究发现：新生儿中性粒细胞（PMN）募集能力低下、抗菌作用不足,与新生儿固有免疫反应缺陷密切相关，进而研究发现新生儿PMN P-选择素糖蛋白配体1（PSGL-1）表达低下，影响PMN的募集能力，并且干预PSGL-1亦导致PMN募集被削弱，但确切机制尚待研究。本项目拟利用临床标本及动物模型进一步分析新生儿PSGL-1的表达与分布对PMN募集与抗菌作用的影响；并通过中和抗体与基因敲除小鼠对PSGL-1干预，分析PSGL-1影响中性粒细胞募集与抗菌作用的机制；同时采用动物体内实验探讨PSGL-1表达缺陷与新生小鼠对病原微生物高易感的确切分子机制。本项目通过阐明PSGL-1干预新生儿脓毒症的作用机制，从而为新生儿脓毒症的免疫干预提供一种新的靶点。

中文关键词： 新生儿脓毒症；PSGL-1；中性粒细胞；募集；固有免疫

英文摘要： Neonates, in contrast to adults, are featured with the defect in their innate immunity-associated antimicrobial responses, which renders them more susceptible to bacterial infection and sepsis. Our previous work has shown that neonates display inefficient innate immune functions, characterized by the impaired polymorphonuclear neutrophil (PMN) recruitment and antimicrobial activity. We further revealed that neonatal PMNs in comparison with adult PMNs exhibited significantly less P-selectin glycoprotein ligand 1 (PSGL-1), leading to diminished PMN chemotaxis and recruitment. Blockage of PSGL-1 in adult PMNs also caused reduced PMN recruitment; however, the precise molecular mechanism involved is still unclear. In this proposed research project, we will use clinical samples and in vitro experiments to investigate the influence of neonatal PSGL-1 expression and distribution on PMN recruitment and PMN-associated bactericidal activity. We will also use the PSGL-1 neutralizing antibody and PSGL-1 knockout mice to clarify the underlying mechanism responsible for PSGL-1-modulated PMN recruitment and antimicrobial activity. Finally, we will use the in vivo animal model to verify the correlation between the defective expression of PSGL-1 and the high vulnerability of neonates to microbial sepsis. By identifying the significance of PSGL-1 in neonatal innate immunity against microbial infection and sepsis, this study will help us to clarify PSGL-1 as a new immuno-therapeutic target for prevention and treatment of microbial sepsis in neonates.

英文关键词： Neonatal sepsis;PSGL-1;PMN;recruitment;innate immune