坏死性小肠炎(NEC)具有很高的致残率和病死率，高发于早产儿及极低体重儿。申请人前期研究表明：粒细胞前体细胞来源的髓系抑制性细胞(PMN-MDSC)与NEC的发生密切相关。新近研究发现：极低体重儿PMN-MDSC中溴素蛋白4(OLFM4)表达水平显著低于健康对照；OLFM4-KO小鼠体内PMN-MDSC水平下降，NEC加重，MDSC关键靶基因S100A9表达下调。据此提出：“OLFM4 通过上调S100A9，促进PMN-MDSC的活化，抑制NEC的发生”。为验证此科学假说，拟首先利用OLFM4蛋白及OLFM4-KO小鼠，研究OLFM4介导S100A9对PMN-MDSC分化及功能的调控机制；进而明确OLFM4通过诱导新生儿PMN-MDSC而抑制NEC的发生；最后分析其临床相关性及病理意义。项目将揭示OLFM4诱导新生儿PMN-MDSC抑制NEC发生的新机制，为NEC的免疫治疗提供新策略。

High incidence of necrotizing enterocolitis (NEC) was observed in premature and low birth weight infants, which has a high rate of disability and mortality. The applicant's preliminary studies have showed that myeloid-derived suppressor cells (MDSCs) from newborn are closely related to the occurrence of NEC. Recent results have found that the function of PMN-MDSC in very low weight baby is lower than that of healthy control, as well as low-expression of olfactomedin 4 (OLFM4) gene; mice with deficiency of OLFM4 displayed lower level of PMN-MDSC, severer NEC symptom and low expression level of S100A9, an important MDSC regulator. Based on these observations, we propose that: “OLFM4 could prevent the development of NEC through inducing the neonatal PMN-MDSC via upregulation of S100A9”. In order to test this proposal, we first study the effect of OLFM4 on the differentiation and activation of PMN-MDSC by OLFM4 protein or knock-out of OLFM4 gene, delineate the signaling pathway of OLFM4 in the regulation of PMN-MDSC; investigate that PMN-MDSC mediates the effect of OLFM4 on NEC. Finally we will explore the clinical significance of PMN-MDSC in NEC, using clinical samples. The implementation of this proposal will reveal the new mechanism of regulating neonatal PMN-MDSC induced by OLFM4 in NEC, and provide a novel strategy for NEC immunotherapy.