Signaling Pathways in Salivary Gland Fluid Secretion

唾液腺液分泌的信号通路

• 批准号: 6962135
• 负责人: Trevor J. Shuttleworth
• 金额: $ 38.61万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6962135
• 关键词: acinar cell; active sites; arachidonate; biological signal transduction; calcium channel; calcium flux; cyclic AMP; electrophysiology; enzyme activity; gene mutation; immunocytochemistry; immunoprecipitation; inositol phosphates; laboratory mouse; mathematical model; molecular biology; muscarinic receptor; parotid gland; phosphorylation; protein kinase A; receptor binding; salivation; western blottings

DESCRIPTION: The inability to produce an adequate secretion of salivary fluid severely impacts general oral health, and the ability for effective speech, and mastication, resulting in conditions that constitute a major health problem for a significant proportion of the population. The focus of this project is to dissect, at the cellular and molecular level, the pathways involved in the effective regulation of salivary fluid secretion. Although the Ca2+- dependent activation of ion channels is the primary mechanism underlying the production of salivary fluid, secretion is significantly enhanced when both Ca2+ and cyclic AMP signaling systems are activated concurrently. Interestingly, cyclic AMP-dependent actions alone produce little or no secretion, but act to augment the normal Ca2+-dependent mechanisms. A significant component of this phenomenon is the potentiation of the Ca2+ signal per se by concomitant increases in cellular cyclic AMP levels. The underlying bases for this process will be examined in mouse parotid acinar cells by investigating - 1) the molecular basis for the cyclic AMP-dependent enhancement of intracellular Ca2+ release via the InsPS receptors; and 2) the characteristics and contributions of agonist-activated Ca2+ entry pathways in Ca2+ signaling, and their modulation by cyclic AMP. As a complement to these experimental studies, we will develop and utilize mathematical modeling approaches to help define the complex spatial and temporal interactions between these two signaling pathways by generating, in an interactive and cooperative manner, unique specific model predictions whose validity can then be tested experimentally. Understanding the molecular basis for this synergism is critical for fully understanding the normal physiology of the gland, and potentially providing key information for the ultimate manipulation of these processes as a means of improving fluid secretion in individuals with salivary hypofunction.

产品说明：无法产生足够的唾液分泌严重影响一般口腔健康，以及有效的言语和咀嚼能力，导致构成相当大比例人口的主要健康问题的状况。这个项目的重点是解剖，在细胞和分子水平上，参与有效调节唾液分泌的途径。虽然离子通道的Ca 2+依赖性激活是唾液产生的主要机制，但当Ca 2+和环AMP信号系统同时激活时，分泌显著增强。有趣的是，单独的环AMP依赖性作用产生很少或没有分泌，但作用于增强正常的Ca 2+依赖性机制。这种现象的一个重要组成部分是通过伴随细胞环AMP水平的增加而增强Ca 2+信号本身。这一过程的基础将在小鼠腮腺腺泡细胞中进行检查，通过研究：1）环AMP依赖性增强细胞内Ca 2+释放通过InsPS受体的分子基础;和2）激动剂激活的Ca 2+进入途径在Ca 2+信号传导中的特征和贡献，以及环AMP对其的调节。作为这些实验研究的补充，我们将开发和利用数学建模方法，以帮助定义这两个信号通路之间复杂的空间和时间的相互作用，通过生成，在一个互动和合作的方式，独特的特定模型预测，其有效性，然后可以通过实验进行测试。了解这种协同作用的分子基础对于充分了解腺体的正常生理学至关重要，并可能为最终操纵这些过程提供关键信息，作为改善唾液功能减退个体液体分泌的手段。