An experimental/computational approach for understanding salivary fluid secretion

摘要 主要唾液腺的分泌物提供水合和润滑口腔的液体，以及 开始消化食物的蛋白质。此外，唾液中也存在保护口腔和 上消化道受到细菌和真菌攻击。唾液腺功能减退(口干) 导致体液流量减少会导致生活质量的严重恶化，并与 自身免疫性疾病、干燥综合征(SS)和头颈部癌症放射治疗后。 口干症导致吞咽和咀嚼食物困难，牙齿携带者显著增加和 对口腔念珠菌病的易感性。开发口干症或“口干”的治疗方法是至关重要的。 了解生理上导致唾液分泌的过程以及这些机制是如何改变的 处于病态。推动这项提议的首要原则是， 实验研究和定量的理论模型可以用来加深我们对 唾液腺生理和病理都不是任何一种单一的方法可以实现的 与世隔绝。在目前的提案中，我们将通过纳入沟通的影响来构建我们的模型 细胞之间通过腺泡中的连接复合体。此外，我们还将生成唾液的3D模型 并将此信息集成到腺泡模型中，以生成解剖学上正确的3D模型 唾液腺分泌物。该方法将使用模型预测之间的迭代测试过程 以及实验确定的参数和结果。这种方法的强大之处在于，该模型可以 用来定量地解释和解释实验得出的数据，但也用来建议进一步 实验并随后预测其结果。然后我们将调查其中的机制 肌醇1，4，5-三磷酸受体功能的改变是早期蛋白分解的结果 SS的模型，影响全球钙信号转导。基于这些信息，我们将调整唾液腺模型以 调查这些事件对体液分泌的影响。最后，我们计划使用该模型来理解和 实验测试照射后将水通道蛋白导入导管细胞后如何导致离子 正常情况下重新吸收离子的细胞分泌和流出的液体，因此不能支持水的运动。基座 在模型预测方面，我们将在实验上测试进一步增强管道单元流体流动的方法。它是 预计该模型最终可能会提出恢复唾液腺功能的新疗法，这将 从传统的纯实验方法论来看，并不是很明显。

Abstract Secretion from the major salivary glands provides both fluid that hydrates and lubricates the oral cavity and proteins that begin to digest food. In addition, factors are also present in saliva that protect the oral cavity and upper gastrointestinal tract from bacterial and fungal assault. Hypo-function (xerostomia) of the salivary glands resulting in a reduction of fluid flow leads to a severe deterioration in the quality of life and is associated with the auto-immune disease, Sjögren’s syndrome (SS) and following radiotherapy for head and neck cancers. Xerostomia results in difficulty swallowing and chewing food and a marked increase in dental carries and susceptibility to oral candidiasis. To develop therapy for xerostomia or “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 isolation. In the current proposal, we will build on our model by incorporating the impact of communication between cells through junctional complexes in the acinus. In addition, we will generate a 3D model of salivary duct function and integrate this information into the acinus model to generate an anatomically correct 3D model of salivary gland fluid secretion. 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 investigate the mechanism whereby alterations in inositol 1,4,5-trisphosphate receptor function as a consequence of proteolysis that occurs early in models of SS, impact global Ca2+ signaling. Based on this information, we will adapt the salivary gland model to investigate the impact of these events on fluid secretion. Finally, we plan to use the model to understand and experimentally test how introduction of aquaporin proteins into duct cells following -irradiation, leads to ion secretion and fluid flow from cells which normally reabsorb ions and thus cannot support water movement. Based on model predictions, we will test experimentally means to further enhance fluid flow from duct cells. It is 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.