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; 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 主要唾液腺的分泌提供了水合和润滑口腔和润滑的液体 开始消化食物的蛋白质。此外，在唾液中也存在因素，以保护口腔和 来自细菌和真菌攻击的上胃肠道。唾液网格的功能低下（切除术） 导致流体流量减少会导致生活质量严重恶化，并且与 自动免疫性疾病，Sjögren综合征（SS）以及对头颈癌的放疗。 静态症会导致困难吞咽和咀嚼食物，并明显增加牙齿携带者和 口服念珠菌病的敏感性。为了开发静态或“口干”的治疗，这在根本上很重要 了解导致唾液分泌的过程以及如何改变这些机制 在病理状态。推动这一建议的总体原则是 实验投资和定量理论建模可用于进一步了解我们对 唾液腺生理和病理学都以两种方法无法完成的方式 隔离。在当前的建议中，我们将通过编码通信的影响来建立我们的模型 通过刺激中的连接络合物之间的细胞之间。此外，我们将生成唾液的3D模型 管道功能并将这些信息集成到Acinus模型中，以生成解剖上正确的3D模型 唾液腺液分泌。该方法将在模型预测之间使用迭代测试的过程 以及实验确定的参数和结果。该方法的力量是模型可以是 用于定量解释和解释实验得出的数据，但也建议进一步提出 实验，随后预测其结果。然后，我们将研究该机制 肌醇1,4,5-三磷酸受体的改变是由于蛋白水解在早期发生的蛋白水解的结果 SS的模型，影响全局CA2+信号传导。基于此信息，我们将调整唾液腺模型 研究这些事件对流体分泌的影响。最后，我们计划使用模型来理解和 通过实验测试如何在辐射后将水通道蛋白蛋白引入导管细胞中，导致离子 通常从通常重新吸收离子的细胞的分泌和流​​体流动，因此无法支持水运动。基于 在模型预测上，我们将测试实验手段，以进一步增强导管细胞的流体流动。这是 设想该模型最终可能提出新的疗法来恢复唾液腺功能，这将 不容易从传统的纯实验方法中证明。