An experimental/computational approach for understanding salivary fluid secretion

了解唾液分泌的实验/计算方法

• 批准号: 10391330
• 负责人: A. JAMES R. SNEYD
• 金额: $ 49.26万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10391330
• 关键词: 3-Dimensional; Acinar Cell; Acinus organ component; Anatomy; Apical; Autoimmune Diseases; Automobile Driving; Biophysics; Calcium; Carrier Proteins; Cell model; Cell physiology; Cells; Clinical Trials; Communication; Complex; Coupled; Coupling; Data; Deglutition; Dental; Deterioration; Development; Duct (organ) structure; Ductal Epithelial Cell; Event; Experimental Models; Family suidae; Fluids and Secretions; Food; Funding; Gap Junctions; Generations; Gland; Goals; Head and Neck Cancer; Human; Hydration status; ITPR1 gene; Individual; Innovative Therapy; Inositol; Investigation; Ion Channel; Ions; Knowledge; Lead; Liquid substance; Major salivary gland structure; Manipulative Therapies; Mastication; Methodology; Microscopy; Modeling; Molecular; Mouth Diseases; Mus; Nature; Oral candidiasis; Oral cavity; Oral health; Osmosis; Outcome; Pathologic; Pathology; Patients; Peptide Hydrolases; Permeability; Physiological; Physiology; Plasma; Predisposition; Process; Property; Proteins; Proteolysis; Quality of life; Radiation exposure; Radiation therapy; Regulation; Resolution; Role; Saliva; Salivary; Salivary Gland Diseases; Salivary Glands; Salivary duct structure; Signal Transduction; Sjogren' s Syndrome; Stimulus; System; Testing; Theoretical model; Tight Junctions; Translating; Upper digestive tract structure; Water; Water Movements; Xerostomia; assault; base; cell type; design; experimental study; fluid flow; improved; irradiation; model development; multi-scale modeling; novel strategies; novel therapeutics; predictive modeling; receptor function; saliva secretion; therapy development; treatment optimization; water channel

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.

抽象的 主要唾液腺的分泌物提供了水合和润滑口腔的液体， 开始消化食物的蛋白质此外，唾液中还存在保护口腔和口腔的因子。 上消化道免受细菌和真菌侵袭，唾液腺功能低下（口干症）。 导致流体流量减少，导致生活质量严重恶化，并与 自身免疫性疾病、干燥综合征 (SS) 以及头颈癌放疗后。 口干症会导致吞咽和咀嚼食物困难以及牙齿脱落和牙齿明显增加。 对口腔念珠菌病的易感性 开发口干症或“口干症”的治疗方法至关重要。 了解导致唾液分泌的生理过程以及这些机制的原理 在病态状态下，推动这一提议的首要原则是协同组合。 实验研究和定量理论模型可用于进一步我们的理解 唾液腺生理学和病理学的方式是单一方法无法实现的 在当前的提案中，我们将通过纳入沟通的影响来构建我们的模型。 此外，我们将生成唾液的 3D 模型。 导管功能并将这些信息集成到腺泡模型中以生成解剖学上正确的 3D 模型 该方法将使用模型预测之间的迭代测试过程。 该方法的强大之处在于该模型可以通过实验确定参数和结果。 用于定量解释和解释实验得出的数据，但也可以进一步提出建议 实验并随后预测其结果，然后我们将研究其机制。 由于早期发生的蛋白水解作用，肌醇 1,4,5-三磷酸受体功能发生改变 SS 模型影响全局 Ca2+ 信号传导 基于此信息，我们将调整唾液腺模型以适应。 最后，我们计划使用该模型来了解和研究这些事件对液体分泌的影响。 实验测试在  辐射后将水通道蛋白引入导管细胞如何导致离子 细胞的分泌和液体流动通常会重新吸收离子，因此不能支持水的运动。 根据模型预测，我们将通过实验方法测试进一步增强导管细胞的流体流动。 设想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中不容易明显看出。