Mechanisms of Gastric Mucosal Transformation in Hip1r-Deficient Mice

摘要 在这个项目中，我们将使用基因工程小鼠模型来探测细胞凋亡的机制。 发展为胃上皮化生和胃癌。亨廷顿蛋白相互作用蛋白1缺陷小鼠 相关的（Hip 1 r）开发一个渐进的和多方面的胃细胞转化。Hip 1 r是 在壁细胞中丰富，在壁细胞中对于与酸分泌相关的囊泡运输是重要的。我们有 最近确定，Hip 1 r缺陷小鼠表现出腺体肥大，壁细胞和主细胞的损失， 异常粘液颈细胞显著扩张（粘液腺化生）。这些特征普遍存在 在2个月大的小鼠中，发育不良，化生和最终的胃窦肿瘤出现在年龄较大的小鼠中， 小鼠（6-8个月）。壁细胞损失导致酸分泌受损，胃泌素增加， 试图使胃酸正常化的稳态反应。我们假设胃泌素的增加是导致 胃酸分泌胃的增殖增加。这将在AIM 1中通过交叉Hip 1 r缺陷 小鼠到胃泌素缺乏小鼠，以辨别这种激素在胃粘膜重塑中的作用。我们 初步研究表明，增加的增殖和肥大是胃泌素依赖性的。另一 缺乏Hip 1 r的胃的主要特征是炎症。初步数据显示， 浸润和增加的干扰素γ作为反应的组成部分。我们最近在本地 干扰素γ受体表达的粘液颈细胞，从而连接细胞因子信号通路， 粘液细胞化生中的关键靶细胞发生改变。在目标2中，我们将检验干扰素 γ和免疫细胞（B和T细胞）通过使Hip 1 r缺陷小鼠杂交， 免疫耗竭的小鼠品系。与分泌酸部分的转化事件有关的是， 胃是胃窦区肿瘤的发展。胃肿瘤的进展与 在人类中的转化事件，包括增加的表达和信号的形态发生素声波 印度刺猬目的3将描述Hip 1 r缺陷小鼠在Hip 1 r基因表达过程中的hedgehog信号传导。 使用hedgehog报告小鼠品系进展为发育不良，并测试是否增加了hedgehog报告小鼠品系的发育不良。 信号传导有助于粘膜转化，使用环巴胺阻断粘膜中的信号传导。 胃此外，刺猬对于肿瘤生长的重要性将在具有环巴胺的培养物中测试。 总之，这些实验将为复杂的细胞变化提供机制性的见解， 与胃壁细胞萎缩和胃酸分泌减少有关。项目叙述 该项目的重点是一种新的小鼠品系，其表现出类似于 在人类胃癌的发展中观察到。目的是确定胃细胞的基本机制， 转化并测试它们在肿瘤形成中的作用。因此，这些研究可能会提供深入了解这一过程 胃癌是人类最常见的癌症死亡原因之一， 国际吧

ABSTRACT In this project we will use genetically engineered mouse models to probe mechanisms of cellular changes that progress to gastric metaplasia and cancer. Mice deficient in Huntingtin interacting protein 1 related (Hip1r) develop a progressive and multifaceted cellular transformation of the stomach. Hip1r is abundant in parietal cells where it is important for vesicular trafficking associated with acid secretion. We have recently determined that Hip1r-deficient mice exhibit glandular hypertrophy, loss of parietal and chief cells, and marked expansion of abnormal mucous neck cells (mucous gland metaplasia). These features are widespread in mice as young as 2 months of age, with dysplasia, metaplasia and eventual antral tumors emerging in older mice (6-8 months). Parietal cell loss results in impaired acid secretion and increased gastrin occurs as a homeostatic response to attempt to normalize acid. We hypothesize that increased gastrin is responsible for increased proliferation of the acid-secreting stomach. This will be tested in AIM 1 by crossing Hip1r-deficient mice to gastrin-deficient mice, to discern the role of this hormone in the remodeling of the gastric mucosa. Our preliminary studies demonstrate that increased proliferation and hypertrophy are gastrin-dependent. Another key feature of the Hip1r-deficent stomach is inflammation. Preliminary data shows widespread immune cell infiltrates and increased interferon gamma as components of the response. We have recently localized interferon gamma receptor expression to the mucous neck cells, thus linking cytokine signaling pathways to the key target cell altered in mucous cell metaplasia. In Aim 2 we will test the hypothesis that interferon gamma and immune cells (B and T cells) induce the cellular transformation by crossing Hip1r-deficient mice to immune-depleted mouse strains. Associated with the transformation events in the acid secreting portion of the stomach is the development of tumors in the antral region. The progression to gastric tumors parallels transformation events in the human, including increased expression and signaling of the morphogens sonic and Indian hedgehog. Aim 3 will characterize hedgehog signaling in Hip1r-deficient mice during the progression to dysplasia using hedgehog reporter mouse strains, and test whether increased hedgehog signaling is contributing to the mucosal transformation with the use of cyclopamine to block signaling in the stomach. In addition, the importance of hedgehog for tumor growth will be tested in culture with cyclopamine. Together these experiments will provide mechanistic insights into the complex cellular changes commonly associated with parietal cell atrophy and low acid secretion in the stomach. PROJECT NARRATIVE This project focuses on a new mouse strain that exhibits classic cellular changes similar to those observed in the development of human gastric cancer. The goal is to define basic mechanisms of stomach cell transformation and test their role in tumor formation. Thus these studies may provide insights into the process of stomach cancer development in human, which is one of the most prevalent causes of cancer death worldwide.