| The primary objective of this research was to investigate the roles of gastrin and histamine in the regulation of acid secretion using genetically engineered mouse models. Previously, gastrin-deficient mice were shown to have an in vivo impairment in acid secretion. The first aim of this project was to test whether the reduction in acid secretion in gastrin-deficient mice was due to an intrinsic defect in parietal cells. Using purified parietal cells and isolated glands, calcium responses and in vitro acid accumulation were analyzed. Surprisingly, calcium levels and acid accumulation were enhanced in comparison to controls, suggesting that gastrin is not required for parietal cells to secrete acid but that it is essential for normal in vivo acid levels. An increase in parietal cell number and a decrease in parietal cell size were also detected, emphasizing the role for gastrin in regulating mucosal cell growth. The second aim was to test whether the alterations in gastrin-deficient mice were age-dependent, since changes in the acid secretory system had been reported with age. While an increase in parietal cell number and mucosal proliferation were detected in young gastrin-deficient mice, these changes were not observed in older mice. Interestingly, acid levels significantly increased with age in both controls and gastrin-deficient mice. The age-dependent alterations in the mutant mice suggested that an early compensatory effect existed that served to counteract low acid levels by increasing parietal cell number. The third aim was to engineer a novel transgenic mouse with elevated parietal cell cAMP levels to investigate the consequences of constitutive stimulation of this signaling pathway in the acid secretory system. Preliminary analysis indicated no alterations in basal acid content; however, plasma gastrin levels were significantly reduced, suggesting that elevated parietal cell CAMP may upregulate acid secretion. In addition, gastric morphology was altered in aged transgenic mice, indicating that long-term elevation of cAMP may result in the loss of parietal cells. In summary, the genetically engineered mouse models utilized in this thesis have allowed the opportunity to investigate the independent affects of gastrin and histamine signaling on the normal regulation of the gastric acid secretory system. |
