Gastrin Regulation of Parietal Cell Function in Mice

胃泌素对小鼠壁细胞功能的调节

• 批准号: 6635218
• 负责人: LINDA C. SAMUELSON
• 金额: $ 23.49万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6635218
• 关键词: cholecystokinin; cyclic AMP; differential display technique; gastric acid; gastrins; gastrointestinal epithelium; gastrointestinal function; gene targeting; genetically modified animals; histamine; histamine receptor; histogenesis; hormone receptor; hormone regulation /control mechanism; laboratory mouse; secretion

DESCRIPTION (Applicant's Abstract): This proposal will examine the regulation of stomach acid secretion and the molecular mechanisms involved in the maturation of the acid secreting parietal cell. It takes advantage of a new gastrin-deficient mouse model produced in this laboratory by gene targeting in embryonic stem cells. With this model, regulatory mechanisms will be investigated in a novel manner since the investigators can control the maturation of the acid secretory system with the exogenous delivery of gastrin. Physiologic analysis of mouse strains that have been functionally altered by transgenic or gene knockout techniques is the basic experimental approach for this grant application. A re-examination of the central question of histamine's specific role in parietal cells stimulation and acid secretion will be tested as a significant component of this proposal. In addition, the applicant will examine the cellular and molecular changes in parietal cells, which take place during their functional maturation. Aim 1 will test the hypothesis that histamine is required for parietal cell maturation in the gastrin-deficient mice. The applicant will stimulate parietal cell maturation in gastrin-deficient mice under conditions where histamine H2 receptor signaling is blocked with a specific antagonist. Aim 2 will test the hypothesis that increased cyclic AMP in parietal cells is sufficient to induce acid secretion in gastrin-deficient mice. This will be achieved by using a newly developed transgenic mouse model designed to chronically upregulate cyclic AMP levels in parietal cells using the cholera toxin Al fragment. Aim 3 will focus on the molecular changes involved with parietal cell maturation. Parietal cells will be tested for CCK-B receptor and histamine H2 receptor function by analysis of intracellular signaling, morphological transformation and acid secretion. Finally, the applicant will use the differential display technique to identify mRNAs whose expression changes in response to gastrin-stimulated maturation of the acid secretory system. A better understanding of the basic biology of acid secretion and parietal cell function will be valuable for further insight into the pathology associated with acid secretion, which remains a significant health problem.

描述（申请人的摘要）：该提案将审查该法规 胃酸分泌及其分子机制 分泌酸的壁细胞的成熟。它利用了一种新的 本实验室通过基因靶向制作胃泌素缺陷小鼠模型 胚胎干细胞。通过这种模式，监管机制将 以新颖的方式进行调查，因为调查人员可以控制 通过外源性输送胃泌素使酸分泌系统成熟。 功能改变小鼠品系的生理分析 转基因或基因敲除技术是基本的实验方法 本补助金申请。重新审视组胺的核心问题 将测试壁细胞刺激和酸分泌的具体作用 作为该提案的重要组成部分。此外，申请人将 检查壁细胞中发生的细胞和分子变化 在其功能成熟期间。目标 1 将检验以下假设： 胃泌素缺乏者的壁细胞成熟需要组胺 老鼠。申请人将刺激壁细胞成熟 组胺 H2 受体信号传导条件下的胃泌素缺陷小鼠 被特定的拮抗剂阻断。目标 2 将检验以下假设： 壁细胞中环磷酸腺苷的增加足以诱导酸分泌 在胃泌素缺乏的小鼠中。这将通过使用新开发的 旨在长期上调环磷酸腺苷水平的转基因小鼠模型 使用霍乱毒素 Al 片段的壁细胞。目标 3 将重点关注 与壁细胞成熟有关的分子变化。壁细胞会 通过分析来测试 CCK-B 受体和组胺 H2 受体功能 细胞内信号传导、形态转化和酸分泌。 最后，申请人将使用差分显示技术来识别 其表达随胃泌素刺激的成熟而变化的 mRNA 酸分泌系统。更好地了解酸的基本生物学 分泌和壁细胞功能对于进一步了解 与酸分泌相关的病理学，这仍然是一个重要的 健康问题。