Signaling Pathways in Salivary Gland Fluid Secretion

描述：无法产生足够的唾液分泌物严重影响一般口腔健康，以及有效说话和咀嚼的能力，导致对相当大比例的人口构成重大健康问题的情况。这个项目的重点是在细胞和分子水平上剖析参与唾液分泌有效调节的途径。虽然钙离子依赖的离子通道激活是唾液产生的主要机制，但当钙离子和环状AMP信号系统同时激活时，唾液分泌显著增强。有趣的是，循环AMP依赖的作用单独产生很少或没有分泌，但作用是增强正常的钙依赖机制。这一现象的一个重要组成部分是伴随着细胞内环磷酸腺苷水平的增加而增强了钙信号本身。这一过程的潜在基础将在小鼠腮腺腺泡细胞中通过研究：1)依赖于环状AMP通过INSPs受体促进细胞内钙释放的分子基础；2)激动剂激活的钙进入通路在钙信号转导中的特征和作用，以及环状AMP对其调节。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，通过以交互和合作的方式生成独特的特定模型预测，帮助定义这两个信号通路之间的复杂空间和时间相互作用，然后可以通过实验测试其有效性。了解这种协同作用的分子基础对于全面了解腺体的正常生理至关重要，并可能为最终操纵这些过程提供关键信息，作为改善唾液功能低下个体体液分泌的一种手段。

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.