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: 7168281
• 负责人: LINDA C. SAMUELSON
• 金额: $ 12.85万
• 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 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7168281
• 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（申请人摘要）：本提案将审查法规 胃酸分泌和参与的分子机制， 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技术制备的胃泌素缺陷小鼠模型， 胚胎干细胞在这种模式下，监管机制将 以一种新颖的方式进行调查，因为调查人员可以控制 酸分泌系统的成熟与外源性胃泌素的递送。 对已经被功能改变的小鼠品系的生理学分析 转基因或基因敲除技术是用于 这份补助申请对组胺的中心问题的重新审视 将测试在壁细胞刺激和酸分泌中的特定作用 作为这一提案的重要组成部分。此外，申请人将 检查壁细胞的细胞和分子变化， 在其功能成熟期。目标1将检验以下假设： 组织胺是胃泌素缺乏的小鼠壁细胞成熟所必需的。 小鼠申请人将刺激壁细胞成熟， 在组胺H2受体信号传导的条件下， 被特定的拮抗剂阻断。目标2将检验以下假设： 壁细胞中增加的环AMP足以诱导酸分泌 在缺乏胃泌素的小鼠中。这将通过使用新开发的 转基因小鼠模型旨在长期上调环磷酸腺苷水平 壁细胞使用霍乱毒素Al片段。目标3将侧重于 与壁细胞成熟有关的分子变化。壁细胞将 通过分析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，申请人将使用差异显示技术来识别 其表达响应于胃泌素刺激的成熟而改变的mRNA， 酸分泌系统。更好地了解酸的基本生物学 分泌和壁细胞功能将有助于进一步了解 与酸分泌相关的病理，这仍然是一个重要的 健康问题。