单核细胞反式提呈IL-6导致肠道Th17过度分化促进新生儿坏死性小肠结肠炎发生发展的机制研究

新生儿坏死性小肠结肠炎（NEC）是新生儿常见的严重胃肠疾病。最近研究证实Th17过度分化是NEC发病的重要病因，但其发生发展机制尚未完全解析。申请人预实验发现患儿单核细胞（Mo）有反式提呈IL-6信号的潜能，还发现该信号可能介导H3K9去甲基化的p-KDM3A高表达，进而与TH17过度分化相关。为此，本项目拟用Duolink-PLA、Chip-Seq、激光共聚焦、组织芯片等技术，在原代细胞、条件性基因敲除小鼠和临床组织样本等不同水平进一步深入探讨“Mo/IL-6—STAT3/KDM3A—Th17过度分化—NEC”这一机制，并通过小分子药物阻断p-KDM3A通路研究其逆转Th17分化治疗NEC的可行性。总之，本项目通过对单核细胞反式提呈IL-6激活p-KDM3A在NEC发病中的作用机制研究，可能为NEC的临床治疗提供新的关键靶点，具有重大的科学意义和临床价值。

Neonatal necrotizing enterocolitis (NEC) is a common severe gastrointestinal disease in newborns. Although recent studies have confirmed that the overdifferentiation of Th17 cell is an important cause of NEC, the specific mechanism of its occurrence and development has not been fully understood. However, our pre-experiment found that the monocytes (Mo) of the NEC patients had the potential of trans-presenting IL-6 signal and this signal might also mediate the high expression of H3K9 demethylated p-KDM3A, which was related to the overdifferentiation of Th17 cell. Based upon these finding, our project intends to further explore the mechanism of " Mo / IL-6—STAT3 / KDM3A— the overdifferentiation of Th17 cell —NEC " at different levels of primary cells, conditional gene knockout mice and clinical tissue samples by using Duolink-PLA, Chip-Seq, laser confocal and tissue microarray techniques and investigate the feasibility of reversing Th17 differentiation to treat NEC by blocking the p-KDM3A pathway with small molecule drugs. In conclusion, this project may provide a new key target for the clinical treatment of NEC through studying the mechanism of Mo trans-presenting IL-6 to activate p-KDM3A in the pathogenesis of NEC, which is of great scientific significance and clinical value.