Gastrin Regulation of Parietal Cell Function in Mice

描述(申请人摘要)：本提案将审查该规定 胃酸分泌和参与胃酸分泌的分子机制 分泌酸性物质的壁细胞成熟。它利用了一种新的 本实验室利用基因打靶技术建立胃泌素缺陷小鼠模型 胚胎干细胞。在这种模式下，监管机制将是 以一种新的方式进行调查，因为调查人员可以控制 胃泌素的外源性递送使酸性分泌系统成熟。 功能改变的小鼠品系的生理分析 转基因或基因敲除技术是 这份拨款申请。对组胺这一中心问题的重新审视 将测试在壁细胞刺激和酸分泌中的具体作用 作为这项提案的一个重要组成部分。此外，申请者将 检查发生在壁细胞中的细胞和分子的变化 在它们的功能成熟过程中。目标1将检验假设 胃泌素缺乏症患者壁细胞成熟需要组胺 老鼠。申请者将刺激壁细胞在 组胺H2受体信号转导条件下的胃泌素缺陷小鼠 被一种特定的拮抗剂阻断。目标2将检验这一假设 壁细胞中环磷酸腺苷的增加足以诱导胃酸分泌 在胃泌素缺乏的小鼠身上。这将通过使用一种新开发的 转基因小鼠慢性上调脑内cAMP水平的研究 使用霍乱毒素Al片段的壁细胞。目标3将重点放在 与壁细胞成熟有关的分子变化。壁细胞会 通过分析CCK-B受体和组胺H2受体功能 细胞内信号、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 胃泌素刺激成熟后表达变化的mRNAs 酸性分泌系统。对酸的基本生物学有更好的了解 分泌物和壁细胞功能将对进一步了解 与胃酸分泌相关的病理，这仍然是一个重要的 健康问题。

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.