ONTOGENY OF GASTRIC ACID SECRETORY REGULATION

拟议的项目旨在研究胃酸的发展。 通过评估胃泌素的生物合成和释放来进行分泌调节， 壁细胞的细胞内转导机制，以及 壁细胞上的胃泌素受体。胃泌素是一种主要的激素 生理上调节酸的分泌。像许多肽荷尔蒙一样，胃泌素 是作为一种大的前体分子合成的 翻译后处理。最重要的一步是 翻译后加工是羧基末端的酰胺化 这使得该分子具有最大的生物学活性。该项目将 通过体内评价胃泌素的作用来评价胃泌素生化 胃肠激素的生物合成和翻译后 胃泌素的加工。平行研究将在体外细胞中设计 系统。培养的犬胃窦细胞将被用来评估个体发育 胃泌素的生物合成及其对胃肠道的直接影响 激素对胃泌素生物合成和释放的影响。使用特定的抗血清治疗 胃泌素的酰胺化羧基末端和甘氨酸的延伸 胃泌素的羧基末端延伸加工中间体 胃泌素的翻译后处理将被评估以响应 治疗。胃泌素特异性mRNA将在组织和 培养细胞作为胃泌素基因表达的测量。有教养的人 G细胞也将被用来评估细胞内机制 胃泌素释放。评价其生物活性的个体发生学 胃泌素及其前体(G-Gly)，将分离的犬壁细胞 获得并定量测定~(14)C氨基比林的摄取量 分泌物。将利用胃肠激素和化学探针 研究cAMP和c-Kinase通路的发育。 用于胃酸分泌。最后，胃泌素和G-Gly的年龄相关性变化 壁细胞受体将通过传导受体结合来阐明 利用分离的壁细胞及其与其相关性的研究 生物活性。因为有记录在案的ACID变化 随着年龄的增长而分泌，了解胃泌素的生物化学，个体发育 壁细胞功能，胃泌素受体的发育可能 有助于阐明酸性分泌调节的发展及其原因 所有物种新生儿的高胃泌素血症。

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.