An experimental/computational approach for understanding salivary fluid secretion

描述（由申请人提供）：唾液的分泌对口腔健康至关重要。液体为口腔提供水合作用和润滑作用，而蛋白质含量提供酶，其开始消化食物，以及保护口腔和上胃肠道免受细菌和真菌感染的额外蛋白质。考虑到这些重要的生理功能，与自身免疫性疾病Sjogren综合征（SS）相关的唾液腺功能减退以及作为头颈癌放疗的结果导致生活质量显著恶化;包括吞咽和咀嚼食物困难以及牙齿携带和对口腔念珠菌病的易感性显著增加。为了开发“口干”的治疗方法，了解生理上导致唾液分泌的过程以及这些机制在病理状态下如何改变是至关重要的。驱动这一建议的总体原则是，实验研究和定量理论建模的协同组合可以用于进一步我们对唾液腺生理学和病理学的理解，这两种方法都不能实现。在目前的建议中，将开发一个多尺度模型的液体分泌的实验数据，它捕获的必要的空间和时间的机械功能所需的流体流动的分子，细胞和腺体水平。该方法将使用模型预测与实验确定的参数和结果之间的迭代测试过程。该方法的强大之处在于，该模型可用于定量解释和解释实验得出的数据，但也可用于建议进一步的实验，并随后预测其结果。然后，我们将使用来自SS患者和小鼠疾病模型的数据来调整模型，首先研究SS中唾液功能低下的分子机制，然后使用模型来预测和实验测试唾液流量如何增加。最后，我们将调整模型，再次忠实地根据实验数据，描述减少唾液腺功能，发生以下g-照射腺泡组织损失之前的唾液腺。据设想，该模型可能最终提出新的治疗方法来恢复唾液腺功能，这将不容易从传统的纯实验方法明显。

DESCRIPTION (provided by applicant): The secretion of saliva is vitally important for oral health. The fluid provides hydration and lubrication to the oral cavity while the protein content contributes enzymes, which begin to digest food, and additional proteins which protect the oral cavity and upper gastrointestinal tract from bacterial and fungal infections. Given these important physiological functions, hypo-function of the salivary glands which is associated with the auto- immune disease, Sjogren's syndrome (SS) and as a result of radiotherapy for head and neck cancers results in a marked deterioration in quality of life; including difficulty swallowing and chewing food and a marked increase in dental carries and susceptibility to oral candidiasis. To develop therapy for "dry-mouth" it is fundamentally important to understand the processes that lead to saliva secretion physiologically and how these mechanisms are altered in pathological states. The overarching principle driving this proposal, is that a synergistic combination of experimental investigation and quantitative theoretical modelling can be used to further our understanding of both salivary gland physiology and pathology in a manner that neither single approach can accomplish. In the current proposal, a multi-scale model of fluid secretion will be developed from experimental data, which captures the essential spatial and temporal mechanistic features required for fluid flow at the molecular, cellular and glandular levels. The approach will use a process of iterative testing between model predictions and experimentally determined parameters and outcomes. The power of the approach is that the model can be used to quantitatively explain and interpret the experimentally derived data but also to suggest further experiments and subsequently to predict their outcomes. We will then adapt the model using data from SS patients and mouse models of disease to first, investigate the molecular mechanisms which underlies salivary hypo-function in SS and then use the model to predict and experimentally test, how salivary flow can be increased. Finally, we will adapt the model, again based faithfully on experimental data, to describe the reduction in salivary gland function that occurs following g-irradiation of salivary glands prior to loss of acinar tissue. It s envisioned that the model may ultimately suggest novel therapies to restore salivary gland function, which would not be readily evident from a traditional purely experimental methodologies.