Signaling Pathways in Salivary Gland Fluid Secretion

唾液腺液分泌的信号通路

• 批准号: 7247963
• 负责人: Trevor J. Shuttleworth
• 金额: $ 35.17万
• 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/7247963
• 关键词: Acinar Cell; Address; Affect; Agonist; Arachidonic Acids; Behavior; Binding; Cells; Characteristics; Chemosensitization; Complement; Complex; Computer Simulation; Condition; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Elevation; Fluids and Secretions; Gland; Health; Human; Individual; Inositol; Investigation; Ion Channel; Liquid substance; Mastication; Modeling; Molecular; Mus; Muscarinic Acetylcholine Receptor; Mutation; Oral health; Outcome; Parotid Gland; Pathway interactions; Phosphorylation; Phosphorylation Site; Physiology; Play; Population; Process; Production; Property; Publishing; Rate; Regulation; Research Personnel; Role; Salivary; Salivary Glands; Shapes; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Site; Speech; System; Techniques; Testing; base; extracellular; improved; in vivo; mathematical model; novel; parotid cell; programs; receptor; research study; response; saliva secretion; synergism; tool

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.

描述：无法产生足够的唾液液分泌严重影响一般的口腔健康，有效的语音和咀嚼能力，导致构成大部分人群的重大健康问题的疾病。该项目的重点是在细胞和分子水平上剖析有效调节唾液液分泌的途径。尽管离子通道的Ca2+依赖性激活是唾液流体产生的主要机制，但是当Ca2+和环状AMP信号系统同时激活时，分泌显着增强。有趣的是，仅循环AMP依赖性作用几乎没有分泌或没有分泌，而是为了增加正常的Ca2+依赖性机制。该现象的一个重要组成部分是通过伴随细胞环状AMP水平增加Ca2+信号本身的增强。该过程的基础碱基将通过研究小鼠腮腺细胞中检查-1）通过INSPS受体释放细胞内Ca2+释放的环状AMP依赖性增强的分子基础； 2）激动剂激活的Ca2+进入途径在Ca2+信号传导中的特征和贡献，以及它们通过环状AMP的调节。作为对这些实验研究的补充，我们将开发和利用数学建模方法，以帮助通过以互动和合作的方式生成这两个信号传导途径之间的复杂空间和时间相互作用，从而可以进行独特的特定模型预测，然后可以对其有效性进行实验测试。了解这种协同作用的分子基础对于完全理解腺体的正常生理学至关重要，并且有可能提供关键信息，以最终对这些过程进行最终操纵，以此作为改善唾液功能不全的人的流体分泌的一种手段。