A MICROSURGICAL INVESTIGATION OF GASTRIC ACID SECRETION

胃酸分泌的显微外科研究

• 批准号: 6381011
• 负责人: John Peter GEIBEL
• 金额: $ 40.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-02-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6381011
• 关键词: acidity /alkalinity; apical membrane; basolateral membrane; gap junctions; gastric acid; genetically modified animals; hormone regulation /control mechanism; hydrogen potassium exchanging ATPase; laboratory mouse; laboratory rat; membrane channels; membrane transport proteins; protein structure function; secretion; tissue /cell culture

The stomach acts as the primary site of digestion of food taken into the body. The ability of the stomach to digest this food is linked to having sufficient substrates for controlled acid secretion, and functional transport proteins at the apical and basolateral membrane of the gastric gland along with sufficient bicarbonate containing mucus at the surface of the stomach to prevent erosion of the membranes due to the released acid. The regulated release of ions is normally controlled by neuronal and hormonal regulatory pathways. However, the exact mechanisms of controlled acid release are not known, as well as a complete characterization of the transport proteins that line the basolateral and apical membranes. The recent discovery of a divalent cation receptor on the basolateral membrane of the gastric gland as well as the identification of an apical Na-H transport protein and a surface cell NBC protein complex have added addition insights into the regulation of acid secretion. The ability to use an intact surface preparation, in combination with the isolated perfused single gastric gland gives important vehicles for studying and modeling the intact tissues. The regulation of these transporters and the transfer of signal information from one cell to the other is of great importance in understanding the complex issues of acid secretion in health and disease. To add to the investigative arsenal we have recently developed transgenic models that will allow direct manipulation of the secretory and regulatory pathways associated with acid secretion in the stomach. The goal of the present application is to classify, and characterize the apical and basolateral membrane associated acid-base transporters and to determine what role the newly identified divalent cation receptor plays in controlling their activity. Special emphasis will be given to the newly identified apical Na-H, and the basolateral Na/HCO3 in the gland and surface cell preparations. Additional studies will also address the role of gap junctions in regulated acid secretion. These studies will include the use of isolated perfused gastric glands, surface cells, and transgenic models to study in detail the importance of the proteins which control acid secretion. The characterization and modulation of transport proteins and receptors will enhance our basic understanding of regulated acid secretion and will play an important role in developing new strategies for the treatment of gastric related illness in the population.

胃是消化进入体内的食物的主要场所。胃消化这种食物的能力与控制胃酸分泌的足够底物、胃腺顶膜和基底外侧膜上的功能性转运蛋白以及胃表面足够的含有碳酸氢盐的粘液有关，以防止由于释放的酸而腐蚀胃膜。离子的调节释放通常由神经元和激素调节途径控制。然而，控制酸释放的确切机制以及基底外侧膜和顶膜转运蛋白的完整特征尚不清楚。最近在胃腺基底外侧膜上发现了二价阳离子受体，以及顶端 Na-H 转运蛋白和表面细胞 NBC 蛋白复合物的鉴定，为酸分泌的调节提供了更多的见解。使用完整表面制剂的能力与分离的灌注单个胃腺相结合，为完整组织的研究和建模提供了重要的工具。这些转运蛋白的调节以及信号信息从一个细胞到另一个细胞的传递对于理解健康和疾病中酸分泌的复杂问题非常重要。为了增加研究手段，我们最近开发了转基因模型，该模型将允许直接操纵与胃酸分泌相关的分泌和调节途径。本申请的目的是对顶膜和基底外侧膜相关的酸碱转运蛋白进行分类和表征，并确定新鉴定的二价阳离子受体在控制其活性中发挥什么作用。将特别强调新鉴定的顶端 Na-H 以及腺体和表面细胞制剂中的基底外侧 Na/HCO3。其他研究还将探讨间隙连接在调节酸分泌中的作用。这些研究将包括使用分离的灌注胃腺、表面细胞和转基因模型来详细研究控制胃酸分泌的蛋白质的重要​​性。转运蛋白和受体的表征和调节将增强我们对调节酸分泌的基本了解，并将在制定治疗人群胃相关疾病的新策略方面发挥重要作用。