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SECRETAGOGUE REGULATION IN PARIETAL CELLS

壁细胞的分泌调节

基本信息

批准号：
3237220
负责人：
IRVIN M MODLIN
金额：
$ 18.98万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1989
资助国家：
美国
起止时间：
1989-05-01 至 1993-04-30
项目状态：
已结题

项目摘要

Although recent advances in receptor characterization have led to the development of new agents, such as the H2 blockers, for the treatment of ulcers, the intracellular mechanisms of gastric secretion remain more obscure. The goal of this investigation is to elucidate the intracellular mechanisms which underly the stimulation of parietal cell secretion by acetylcholine and histamine. In essence, we intend to use protein phosphorylation as a tool to study the physiology of a polarized secretory cell system - the parietal cell. We will, firstly, study the stimulation pf protein phosphorylation by histamine in isolated rabbit parietal cells, correlating the magnitude and temporal scale of phosphorylation with the course of acid secretion (aminopyrine uptake), intrinsic factor secretion and intracellular cAMP levels. Secondly, we will confirm the role of histamine in the stimulation of cAMP-dependent phosphorylation through the use of direct stimulatory and inhibitory probes. Thirdly, we will investigate carbachol stimulation of protein phosphorylation correlating :he magnitude and temporal course of secretion inositol triphosphate levels and intracellular calcium fluxes. Fourthly, we will compare the patterns of protein phosphorylation stimulated by histamine and carbachol in order to evaluate points of divergence and confluence in their stimulation of secretion. Fifthly, we will investigate the mechanisms of physiological and pharmacological inhibitors of parietal cell secretion through their effects on secretion, phosphorylation and intracellular messengers. Sixthly, we will investigate the role of protein phosphorylation in the initiation and maintenance of the morphological alterations necessary for secretion. Finally, we will undertake the purification of phosphoprotein substrates in order to investigate the precise localization and function of histamine and carbachol stimulated phosphoproteins. This protocol will allow us to elucidate basic mechanisms underlying coordinate stimulatory pathways for activation of parietal cell secretion. Elucidation of the intracellular mechanisms of secretion may yield insights with therapeutic ramifications as significant as those derived from the delineation of H2-receptor agents.

尽管受体表征的最新进展导致了新药物的开发，如H2阻滞剂，用于胃溃疡的治疗及其细胞内机制分泌物仍然比较模糊。这次调查的目的是以阐明细胞内机制，这些机制是乙酰胆碱和胆碱对壁细胞分泌的刺激作用组胺。从本质上讲，我们打算使用蛋白质磷酸化作为研究极化分泌细胞生理学的工具系统--壁细胞。我们会首先研究组胺刺激体外培养的Pf蛋白磷酸化兔顶细胞，相关的大小和时间尺度伴随着酸分泌过程的磷酸化(氨基比林摄取)、内源性因子分泌和细胞内cAMP水平。其次，我们将确认组胺在刺激中的作用 CAMP依赖的磷酸化通过使用直接刺激性和抑制性探针。第三，我们将调查卡巴胆碱对蛋白质磷酸化的刺激作用三磷酸肌醇的分泌量和时间进程水平和细胞内钙通量。第四，我们将比较组胺刺激的蛋白质磷酸化模式和卡巴胆碱，以评估分歧点和汇合点刺激它们的分泌。第五，我们将调查血管紧张素转换酶生理和药理抑制剂的作用机制壁细胞通过它们对分泌的影响而分泌，磷酸化和细胞内信使。第六，我们将研究蛋白质磷酸化在启动过程中的作用以及维持必要的形态改变分泌物。最后，我们将承担提纯为了研究磷蛋白底物的精确组胺和卡巴胆碱受刺激后的定位和功能磷蛋白。这份协议将使我们能够澄清基本的协调刺激通路的潜在机制激活壁细胞分泌。澄清：分泌的细胞内机制可能会产生关于治疗上的影响与那些源自 H_2受体药物的描述。