An experimental/computational approach for understanding salivary fluid secretion

描述（申请人提供）：唾液的分泌对口腔健康至关重要。这种液体为口腔提供水合作用和润滑，而其中的蛋白质含量则有助于消化食物的酶，以及保护口腔和上消化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，唾液腺功能低下与自身免疫性疾病，干燥综合征（SS）相关，并作为头颈部癌症放疗的结果，导致生活质量明显恶化；包括吞咽和咀嚼食物困难，牙齿携带明显增加，易患口腔念珠菌病。为了开发“口干”的治疗方法，了解导致唾液分泌的生理过程以及这些机制在病理状态下如何改变是至关重要的。推动这一建议的首要原则是，实验研究和定量理论建模的协同结合可以用来进一步了解唾液腺生理学和病理学，这是任何一种方法都无法完成的。在目前的建议中，将从实验数据中开发一个多尺度的液体分泌模型，该模型捕获了液体在分子、细胞和腺体水平上流动所需的基本空间和时间机制特征。该方法将在模型预测和实验确定的参数和结果之间使用一个迭代测试过程。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，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SS患者和小鼠疾病模型的数据来调整模型，首先研究SS唾液功能低下的分子机制，然后使用该模型预测和实验测试唾液流量如何增加。最后，我们将调整模型，再次忠实地基于实验数据，以描述在腺泡组织丢失之前唾液腺g照射后发生的唾液腺功能下降。据设想，该模型可能最终提出恢复唾液腺功能的新疗法，这从传统的纯实验方法中是不容易证明的。

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.