Signaling Mechanisms Promoting Barrett’s Metaplasia

项目摘要 Barrett食管（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，驱动BE起始的细胞和分子机制以及 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。 用于治疗病理实体的靶点。这个应用程序将建立在我们最近的发现， 在小鼠遗传学和人类类器官中，过渡性基底干细胞有助于Barrett化生 模型我们将研究这种独特的干细胞促进肠分化的分子机制 人口我们的初步数据表明，Wnt信号及其下游靶点SOX 4发挥关键作用， BE的发病机制。因此，我们将检验Wnt/SOX 4轴促进巴雷特氏病的假设。 轴的药理学抑制阻断BE进展。我们设计了三个目标 为了验证这一假设：（1）为了验证慢性炎症时增加的Wnt信号传导的假设， 促进过渡性基底干细胞的巴雷特化生。(2)为了验证SOX 4介导 Wnt信号传导促进Barrett化生，和（3）干预Wnt/SOX 4轴以获得治疗效果 与EAC和EA。我们将使用多种小鼠模型（例如Wnt和SOX 4功能获得和丧失） 结合类器官和体外试验来解决这些目标，并测试通过以下方法鉴定的候选药物： 无偏见的屏幕这项工作将提供新的见解的细胞和分子机制的基础 BE的启动和进展，以及我们确定的信号程序将能够发现新的 治疗目标

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.