胃壁细胞Slc26a9基因缺失致使胃黏膜自身免疫失调及上皮细胞转化导致胃粘膜损伤的机制研究

壁细胞缺失导致胃黏膜损伤是胃癌及胃I型神经内分泌肿瘤发生的基础。既往研究发现Slc26a9基因参与CD4+T细胞介导的自身免疫性疾病，我们报道了Slc26a9基因缺失导致胃癌的发生发展。近期研究发现胃壁细胞特异性Slc26a9基因敲除后促使CD4+T细胞聚集并释放炎症介质INFγ，IL-17和IL-2，激活Fas信号通路上调导致小鼠自身免疫性胃炎的发生；继之下调SHH信号通路，出现胃黏膜损伤表型：粘液细胞化生（SPEM和肠化生）和神经内分泌细胞增生。Slc26a9在人自身免疫性胃炎和I型神经内分泌肿瘤中表达显著下调。由此我们提出Slc26a9基因缺失致使胃黏膜自身免疫失调及上皮细胞转化导致胃黏膜损伤发生的科学假说。本研究拟从胃壁细胞Slc26a9基因敲除动物模型水平、单细胞水平（胃Organoid、胃上皮细胞）及人体标本多层面系统研究Slc26a9基因缺失导致胃黏膜损伤发生的机制。

Parietal cell loss induced gastric mucosa injury is the basis of gastric cancer and I type gastric neuroendocrine tumor occurrence. Previous studies showed that Slc26a9 gene was involoved in the CD4+T cell mediated autoimmune diseases. We firstly reported that Slc26a9 gene deficiency caused the development and progression of gastric cancer （The Faseb J. 2015）. Recently, we found that specific parietal cell Slc26a9 gene deletion in mice resulted in activation of CD4+ T cell mediated inflammatory cytokines release, including INFγ，IL-17 and IL-2, as well as activation of Fas signaling pathway. Moreover, downregulation of Shh signaling pathway caused gastric mucosa injury phenotype including SPEM, intestinal metaplasia and neuroendocrine cell hyperplasia. Furthermore, Slc26a9 mRNA and protein expression was significantly decreased in the autoimmune gastritis and I type gastric neuroendocrine tumor tissues when compared with health control. Therefore, we speculated that Slc26a9 targeted deletion in parietal cells induced gastric mucosa autoimmune dysregulation and epithelia cell transformation to cause gastric mucosa injury. In this study, parietal cell specific Slc26a9 gene deletion mouse model and gastric organoid model were established, human autoimmune gastritis and I type gastric neuroendocrine tumor tissues were collected to analysis Slc26a9 mRNA and protein expression. Additionally, gene microarray and bioinformatics analysis etc. will be performed to explore the role of Slc26a9 gene in the pathogenesis of gastric mucosa injury.