胃粘膜肠上皮化生是胃癌最重要的癌前病变。胆汁酸是导致胃上皮细胞肠化生的重要原因，但机制尚不清楚。转录因子CDX2是肠上皮发育分化中的关键分子，其在胃上皮细胞中异常表达可能是肠化生起始的关键步骤。申请者通过建立胆汁酸诱导胃上皮细胞肠化模型，证实胆汁酸刺激可导致胃上皮细胞CDX2激活，且早于其他肠上皮特异分子标志表达。我们由此推测：胆汁酸通过诱导胃上皮细胞CDX2活化，引起一系列分子事件，最终导致肠上皮化生。本项目拟通过转录因子结合位点分析、启动子报告基因等实验研究胆汁酸-CDX2信号转导途径；利用构建慢病毒载体、RNA干扰等方法确定CDX2在胆汁酸诱导肠化生中的作用；联用ChIP-on-chip和表达谱芯片筛选CDX2下游靶基因并验证其功能，以期初步阐明胆汁酸活化CDX2诱导胃粘膜细胞肠化生的分子机制，深化对癌前病变的认识，为理解胃癌发生并制定早期干预对策提供理论和实验支持。

Gastric intestinal metaplasia is the most important precancerous lesion of gastric cancer. It is reported that stimulation of bile acids results in gastric intestinal metaplasia; however, the underlying mechanism remains unclear. Recently, the activation of CDX2 has been found to play an important role in the development and differentiation of intestinal epithelial cell. Our previous work confirmed that gastric epithelium cells, after being treated with bile acids, highly expressed CDX2 and the intestinal molecular markers; the expression of CDX2 was early than the other markers. We thus hypothesize that bile acid induce the gastric intestinal metaplasia through activation of CDX2. This program aim to explore the relationship between CDX2 and bile acid signaling pathway using bioinformatics technological methods and reporter gene assays, to study the function of CDX2 in intestinal metaplasia using lentiviral vectors infection and RNA interference, to screen the CDX2 downstream effectors using ChIP-on-chip and genome microarray profiling. This program would be helpful to elucidate the molecular mechanism of CDX2 mediated gastric intestinal metaplasia induced by bile acid stimulation, deepen the understanding of gastric precancerous lesions, and provide theoretical and experimental support to the early intervention of gastric cancer.