胃上皮细胞外泌体诱导巨噬细胞S100A4表达促进幽门螺杆菌感染胃黏膜炎症的机制研究

幽门螺杆菌（Hp）感染与慢性胃炎、胃溃疡以及胃癌等疾病的发生密切相关，但其致病机制尚未完全阐明。前期研究发现：①Hp感染患者和小鼠胃黏膜可见大量巨噬细胞聚集，且伴有S100A4蛋白表达增高及其上游miR187表达减少；②Hp感染的胃上皮细胞外泌体内具有调控miR187功能的长链非编码RNA（KCNQ1OT1）丰度增加。已知S100A4具有较强的促炎症作用。本项目拟：利用胃炎和胃癌临床标本及Hp感染小鼠模型，探索S100A4高表达的机制及临床意义；明确胃上皮细胞外泌体对巨噬细胞的影响及其机制；在离体和在体条件下，揭示KCNQ1OT1-miR187-S100A4轴在Hp感染所致胃黏膜慢性炎症的分子机制；利用S100A4基因敲除小鼠和胃类器官，研究S100A4通过NF-κB通路的促炎作用；探索S100A4抑制剂对Hp感染胃疾病的治疗作用。本研究将为Hp感染相关疾病的预防和治疗提供新的靶点。

Helicobacter pylori (H.pylori) infection is a growing public health problem. It is well-established that H.pylori infection is closely related to the occurrence of chronic gastritis, peptic ulcer and gastric cancer, the underlying molecular mechanisms, however, are not fully characterized. Here, our preliminary result illustrated that macrophages accumulated abundantly in gastric mucosa of H.pylori infected patients or mice models, along with the substantial overexpression of S100A4 and decreased mir187 expression. Whole transcriptome resequencing of exosomes from H.pylori infected GES-1 elucidated the statistically increased expression of lncRNA-KCNQ1OT1，which can mediate the function of mir187. Recent studies indicated that S100A4 can effectively trigger the cascade of inflammation in multiple disorders, it is of great significance to clarify the function of S100A4 in H.pylori related diseases. In this study, we will firstly investigate the significance of the overexpression of S100A4 after H.pylori infection and the effects of exosomes from H.pylori infected GES-1 on macrophages. Then, we will validate the significance of KCNQ1OT1-miR187-S100A4 axis in gastric mucosal inflammation caused by Hp infection in vitro and in vivo. Finally, we will verify the effects of S100A4 on gastric mucosal inflammation via the activation of NF-κB signaling pathways using H.pylori-infected mice models, S100A4 null mice and gastric organoids, and explore the therapeutic effect of inhibitor of S100A4 on H.pylori-infected diseases.This study may open up new avenues for the prevention and treatment of H. pylori-related gastritis or even gastric cancer.