Signaling Mechanisms Promoting Barrett’s Metaplasia

项目总结 巴雷特食道(BE)是唯一已知的食管腺癌(EAC)癌前病变。 发病率增加了600%。然而，细胞和分子机制推动BE的启动和 进展仍不确定，知识差距使我们无法确定有意义的治疗方法。 病理实体的治疗靶点。这项申请将建立在我们最近的发现基础上，即小说 过渡性基底干细胞在小鼠遗传学和人类类器官巴雷特化生中的作用 模特们。我们将研究独特干细胞促进肠道分化的分子机制 人口。我们的初步数据表明，Wnt信号及其下游靶标Sox4起着关键作用 在BE的发病机制中起重要作用。因此，我们将检验WNT/Sox4轴促进Barrett‘s的假设 化生和轴的药物抑制阻止了BE的进展。我们设计了三个目标 检验这一假说：(1)检验Wnt信号在慢性炎症中增加的假说 促进过渡性基底干细胞的巴雷特化生。(2)检验Sox4中介的假设 WNT信号促进Barrett化生，以及(3)干预Wnt/Sox4轴以获得治疗收益 对抗BE和EAC。我们将使用多种鼠标型号(例如WNT和Sox4增减功能) 与有机化合物和体外测试相结合，以实现这些目标并测试通过 一个没有偏见的屏幕。这项工作将提供对潜在的细胞和分子机制的新见解 BE的启动和发展，以及我们确定的信号程序将使新的发现成为可能 治疗靶点。

PROJECT SUMMARY Barrett’s esophagus (BE) is the only known pre-cancer lesion of esophageal adenocarcinoma (EAC) which has seen a 600% increase in incidence. However, the cellular and molecular mechanism driving BE initiation and progression remains undetermined, and the knowledge gap prevents us from identifying meaningful therapeutic targets for the treatment of the pathological entity. This application will build on our recent findings that the novel transitional basal stem cells contribute to Barrett’s metaplasia in both mouse genetics and human organoid models. We will study the molecular mechanism promoting the intestinal differentiation of the unique stem cell population. Our preliminary data suggest that Wnt signaling and its downstream target SOX4 play critical roles in the pathogenesis of BE. Therefore we will test the hypothesis that the Wnt/SOX4 axis promotes Barrett’s metaplasia and that pharmacological inhibition of the axis blocks BE progression. We have designed three aims to test this hypothesis: (1) To test the hypothesis that increased Wnt signaling upon chronic inflammation promotes Barrett’s metaplasia of transitional basal stem cells. (2) To test the hypothesis that SOX4 mediates Wnt signaling to promote Barrett’s metaplasia, and (3) To intervene in the Wnt/SOX4 axis for therapeutic gain against BE and EAC. We will use multiple mouse models (e.g. Wnt and SOX4 gain- and loss-of-function) combined with organoid and in vitro assays to address these aims and test candidate drugs identified through an unbiased screen. This work will provide novel insights into the cellular and molecular mechanisms underlying the initiation and progression of BE, and the signaling program we identified will enable discovery of new therapeutic targets.