An experimental/computational approach for understanding salivary fluid secretion

描述(申请人提供)：数百万美国人的生活质量受到唾液腺功能障碍的不利影响。据估计，美国有高达20%的成年人会患口干症。这种慢性病的发病率非常高，在极端情况下会导致营养不良。产生足够水平唾液的能力下降与许多主观和客观功能缺陷有关，包括口腔干燥感(口干症)；说话、咀嚼和吞咽困难；以及对龋齿和机会性感染(例如白色念珠菌)的易感性增加。治疗往往只有部分有效，经常产生不良副作用，通常需要终生服用。改进这些治疗的重要第一步是彻底了解参与分泌的分子途径。虽然我们对外分泌腺的功能和调节的了解已经取得了实质性的进展，但我们的知识仍然存在重大差距。特别是，我们还没有得到一个清晰的图景，信号通路和效应分子之间需要协同作用来调节唾液腺产生液体。我们将使用一个多尺度的数学和计算模型来解决这个问题。与纯粹的实验工作不同，这样的数学模型能够提供对复杂系统的行为如何取决于其组成元素的行为的总体理解。首先，我们将建立单个腮腺腺泡和导管细胞的模型，并将这些模型耦合到单个腺泡和相关导管的原型分泌单位的大型模型中。然后，该模型将根据一大组现有的实验结果进行验证和测试，并将用于开发进一步的实验，以测试有关唾液腺功能和调节的假说。特别是，我们将研究细胞间耦合如何影响唾液分泌，分泌如何依赖于各种离子通道的空间位置和功能，以及细胞内钙浓度的波动如何影响唾液分泌。项目简介：唾液腺功能障碍是数百万人的问题，对他们的生活质量有重大影响。尽管存在一些治疗方法，但由于我们对唾液分泌是如何控制的确切了解有限，改进的治疗方法的发展受到了阻碍。我们将结合实验研究和计算模型来研究唾液分泌和控制的机制，并用这个模型来指导更多的实验。

DESCRIPTION (provided by applicant): The quality of life for millions of Americans is adversely affected by salivary gland dysfunction. It is estimated that up to 20% of adults in the US will suffer from xerostomia. The morbidity of this chronic condition is very high, leading in extreme cases to malnourishment. The decreased ability to produce adequate levels of saliva has been associated with numerous subjective and objective functional deficits including the sensation of oral dryness (xerostomia); difficulty with speaking, mastication and swallowing; and an increased susceptibility to caries development and opportunistic infections (e.g., Candida albicans). Treatments are often only partially effective, frequently producing adverse side-effects and usually requiring life-long use. An important first step in improving these treatments is a thorough understanding of the molecular pathways involved in secretion. While substantial advances have been made in our understanding of exocrine gland function and regulation, there remain significant gaps in our knowledge. In particular, we have not yet achieved a clear picture of the synergisms required among signaling pathways and effector molecules to modulate fluid production from salivary glands. We shall address this problem using a multi-scale mathematical and computational model. Unlike purely experimental work, such mathematical models are able to provide an overall understanding of how the behavior of a complex system depends on the behaviors of its constituent elements. Initially we shall develop models of individual parotid acinar and duct cells, and couple these models into a large-scale model of a prototypical secretory unit of a single acinus and associated duct. The model will then be validated and tested against a large set of existing experimental results, and will be used to develop further experiments to test hypotheses about salivary gland function and regulation. In particular, we will examine how intercellular coupling affects salivary secretion, how secretion depends on the spatial positioning and functioning of the various ion channels, and how oscillations in the intracellular calcium concentration affect saliva secretion. Project Narrative: Salivary gland dysfunction is a problem for millions of people, with a significant impact on their quality of life. Although some treatments exist, development of improved therapies is hampered by our limited understanding of exactly how saliva secretion is controlled. We shall combine experimental investigations with a computational model to study the mechanisms of saliva secretion and control, and use this model to guide additional experiments.