Mechanisms of Gastric Mucosal Transformation in Hip1r-Deficient Mice

Hip1r缺陷小鼠胃粘膜转化机制

• 批准号: 8050179
• 负责人: LINDA C. SAMUELSON
• 金额: $ 30.88万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8050179
• 关键词: Achlorhydria; Acids; Age-Months; Animals; Antral; Atrophic; B-Lymphocytes; Cancer Etiology; Cell Lineage; Cells; Cessation of life; Chief Cell; Chronic; Complex; Cytokine Signaling; Data; Development; Dysplasia; Environment; Epithelial Cell Proliferation; Epithelium; Erinaceidae; Event; Exhibits; Galactosidase; Gastric Metaplasia; Gastric Parietal Cells; Gastric mucosa; Gastrins; Gastritis; Genes; Genetically Engineered Mouse; Gland; Goals; Hormones; Human; Human Development; Hyperplasia; Hypertrophy; Hypochlorhydria; Immune; Infection; Inflammation; Inflammation Mediators; Inflammatory; Interferon Type II; Interferons; Link; Mediator of activation protein; Mesenchyme; Metaplasia; Metaplastic; Modeling; Mouse Strains; Mucous Membrane; Mucous body substance; Mus; Neck; Pathway interactions; Play; Process; Proteins; Rag1 Mouse; Reporter; Role; Signal Pathway; Signal Transduction; Stomach; Stomach Neoplasms; T-Lymphocyte; Testing; Time; Transgenic Mice; autoimmune gastritis; base; cell transformation; cell type; cyclopamine; cytokine; human Huntingtin protein; inhibitor/antagonist; insight; interferon gamma receptor; interferon gamma receptors; malignant stomach neoplasm; metaplastic cell transformation; microbial; morphogens; mouse model; mutant; null mutation; public health relevance; receptor expression; research study; response; smoothened signaling pathway; spasmolytic polypeptide; trafficking; tumor; tumor growth

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：在这个项目中，我们将使用基因工程小鼠模型来探讨进展为胃化生和癌症的细胞变化机制。缺乏亨廷顿蛋白相互作用蛋白 1 相关蛋白 (Hip1r) 的小鼠会出现渐进性、多方面的胃细胞转变。 Hip1r 在壁细胞中含量丰富，对于与酸分泌相关的囊泡运输非常重要。我们最近确定Hip1r缺陷小鼠表现出腺体肥大、壁细胞和主细胞丧失以及异常粘液颈细胞显着扩张（粘液腺化生）。这些特征在 2 个月大的小鼠中普遍存在，而在年长的小鼠（6-8 个月）中则出现发育不良、化生和最终出现​​胃窦肿瘤。壁细胞损失导致胃酸分泌受损，胃泌素增加是试图使胃酸正常化的稳态反应。我们假设胃泌素的增加导致胃酸分泌的胃增殖增加。这将在 AIM 1 中进行测试，通过将 Hip1r 缺陷小鼠与胃泌素缺陷小鼠杂交，以辨别这种激素在胃粘膜重塑中的作用。我们的初步研究表明，增殖和肥大的增加依赖于胃泌素。 Hip1r 缺陷胃的另一个主要特征是炎症。初步数据显示，免疫细胞广泛浸润，干扰素γ增加是反应的组成部分。我们最近将干扰素γ受体表达定位于颈部粘液细胞，从而将细胞因子信号传导途径与粘液细胞化生中改变的关键靶细胞联系起来。在目标 2 中，我们将测试干扰素 γ 和免疫细胞（B 细胞和 T 细胞）通过将 Hip1r 缺陷小鼠与免疫耗竭小鼠品系杂交来诱导细胞转化的假设。与胃酸分泌部分的转化事件相关的是胃窦区肿瘤的发展。胃肿瘤的进展与人类的转化事件相似，包括形态发生素 sonic 和 Indian Hedgehog 的表达和信号传导增加。目标3将使用hedgehog报告小鼠品系来表征Hip1r缺陷小鼠在发育不良过程中的hedgehog信号传导，并使用环杷明阻断胃中的信号传导来测试增加的hedgehog信号传导是否有助于粘膜转化。此外，刺猬对肿瘤生长的重要性将在环巴明培养物中进行测试。这些实验将共同提供对通常与壁细胞萎缩和胃酸分泌低相关的复杂细胞变化的机制见解。 公共健康相关性：该项目重点关注一种新的小鼠品系，该品系表现出与人类胃癌发展过程中观察到的经典细胞变化类似的变化。目标是确定胃细胞转化的基本机制并测试它们在肿瘤形成中的作用。因此，这些研究可能有助于了解人类胃癌的发展过程，胃癌是全世界癌症死亡的最常见原因之一。