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.
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