微环境失调导致干细胞异常分裂是肿瘤发生的重要原因。前期我们首次发现了胃窦部存在CCK2R+干细胞，并明确了它具有特异性诱发肠型胃癌的作用。进一步发现肿瘤发生时微环境中Notch信号被激活，并伴随G细胞/胃泌素水平下调，这一系列微环境失调与CCK2R+干细胞来源胃癌相关，但具体作用机制仍待探讨。为此我们提出假说：激活的Notch信号可能通过抑制下游的G细胞/胃泌素，诱发CCK2R+干细胞分裂失衡，从而促进肠型胃癌发生。本项目拟采用已经建立的胃泌素及Notch转基因小鼠，通过H.felis/MNU胃癌模型模拟肿瘤发生时微环境的变化，结合谱系追踪及干细胞培养等技术，从动物模型、分子及细胞水平多方面验证假说，旨在阐述微环境中Notch-G细胞/胃泌素轴调节CCK2R+干细胞参与肠型胃癌发生的作用机制，并初步探索以Notch信号和胃泌素为靶点的治疗方法，以期为胃癌的临床防治提供新而有效的策略。

The imbalance of stem cell division is an important reason for the occurrence of tumor. We have made clear that the CCK2R+ antral stem cells play a specific role in inducing intestinal-type gastric cancer. In further, we found Notch signaling was activated constantly during tumor development, associated with decreased G cells number and lower expression level of gastrin, which may closely regulate CCK2R+ stem cell derived tumor. However, the exact mechanism remains to be elucidated. To this end the hypotheses of this project is that the activation of Notch signaling could inhibit downstream G cells/gastrin, which induced CCK2R + stem cells imbalance, thus promoting intestinal-type gastric cancer. This project intends to adopt established gastrin and Notch transgenic mice, use H.felis/MNU model to mimic the micro-environment changes during gastric tumor development, and then combine with linage tracing and stem cell culture techniques to test the hypothesis on animal models, cellular and molecular level. The aims of this project is to elaborate micro-environmental mechanism of Notch-G cells/gastrin axis regulated CCK2R + stem cells in intestinal-type gastric cancer, and target the Notch signaling and gastrin to explore effective strategies for the prevention of gastric cancer.