The proposed project is designed to study the development of gastric acid secretory regulation by evaluating the biosynthesis and release of gastrin, the intracellular transduction mechanisms of the parietal cell, and the gastrin receptor on the parietal cell. Gastrin is the major hormone that physiological regulates acid secretion. Like many peptide hormones gastrin is synthesized as a large precursor molecule which undergoes post-translational processing. The most important step in the post-translational processing is the amidation at the carboxyl terminus which makes the molecule maximally biologically active. The project will assess gastrin biochemistry by evaluating in vivo the role of gastrointestinal hormones on the biosynthesis and post-translational processing of gastrin. Parallel studies will be designed in vitro cell systems. Cultured canine antral cells will be used to assess the ontogeny of gastrin biosynthesis and the direct effects of these gastro-intestinal hormones on gastrin biosynthesis and relase. Using antisera specific for the amidated carboxyl terminus of gastrin and for the glycine extended carboxyl terminally extended processing intermediates of gastrin, the post-translational processing of gastrin will be assessed in response to treatment. Gastrin specific mRNA will be quantitated in tissue and cultured cells as a measurement of gastrin gene expression. The cultured G-cells will also be used to evaluate the intracellular mechanisms for gastrin release. To evaluate the ontogeny of the biological activity of gastrin and its precursors (G-gly), isolated canine parietal cells will be obtained and 14C aminopyrine uptake quantitated as a measurement of acid secretion. Gastrointestinal hormones and chemical probes will be utilized to examine the development of the cAMP and c-Kinase pathways responsible for acid secretion. Finally, age related changes in gastrin and G-gly parietal cell receptors will be clarified by conducting receptor binding studies using the isolated parietal cells and correlated with their biological activity. Because there are documented changes in acid secretion with age, understanding the biochemistry of gastrin, the ontogeny of parietal cell function, and the development of the gastrin receptor may help to clarify the development of acid secretory regulation and the cause of hypergastrinemia in the newborns of all species.
| Marino, L R (1993) Characterization of the mouse carbonic anhydrase II gene promoter. J Biol Chem 268:7081-9 |
| Marino, L R; Takeuchi, T; Dickinson, C J et al. (1991) Expression and post-translational processing of gastrin in heterologous endocrine cells. J Biol Chem 266:6133-6 |
| Dickinson, C J; Marino, L; Yamada, T (1990) Inhibition of the alpha-amidation of gastrin: effects on gastric acid secretion. Am J Physiol 258:G810-4 |
| Marino, L R; Muglia, B H; Yamada, T (1990) H(+)-K(+)-ATPase and carbonic anhydrase II gene expression in the developing rat fundus. Am J Physiol 259:G108-15 |
| Marino, L R; Sugano, K; Yamada, T (1988) Development of gastrin synthesis and posttranslational processing mechanisms in rats. Am J Physiol 254:G87-92 |
