An experimental/computational approach for understanding salivary fluid secretion

了解唾液分泌的实验/计算方法

基本信息

批准号：
8984828
负责人：
A. JAMES R. SNEYD
金额：
$ 39.85万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-15 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8984828
关键词：
Acinar Cell Apoptosis Automobile Driving Bacterial Infections Behavior Cell Death Cells Data Defect Deglutition Dental Deterioration Development Disease Duct (organ) structure Ductal Ensure Enzymes Experimental Models Exposure to Fluids and Secretions Food Functional disorder Generations Gland Goals Head and Neck Cancer Health Human Hydration status ITPR1 gene Immune System Diseases Infiltration Innovative Therapy Investigation Ion Channel Knowledge Lead Liquid substance Lubrication Lymphocyte Mastication Methodology Modeling Molecular Mus Mycoses Oral candidiasis Oral cavity Oral health Outcome Pathology Patients Physiological Physiology Predisposition Process Production Proteins Quality of life Radiation Radiation therapy Research Ryanodine Receptor Calcium Release Channel Saliva Salivary Salivary Gland Diseases Salivary Glands Signal Transduction Sjogren&apos s Syndrome Syndrome System Testing Theoretical model Therapeutic Time Tissues Trees Upper digestive tract structure Work Xerostomia base cell type design fluid flow irradiation loss of function markov model mathematical model model development mouse model multi-scale modeling novel novel strategies novel therapeutics parotid cell research study saliva secretion salivary acinar cell therapy development

项目摘要

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.

描述（由申请人提供）：唾液的分泌对于口腔健康至关重要。液体为口腔提供水合和润滑，同时蛋白质含量会促进酶，这些酶开始消化食物，并保护口腔和上胃肠道的其他蛋白质免受细菌和真菌感染的影响。鉴于这些重要的生理功能，与自身免疫疾病，Sjogren综合征（SS）相关的唾液腺功能不全，以及由于头颈癌的放疗而导致生活质量的显着恶化；包括难以吞咽和咀嚼食物，以及牙齿携带和对口服念珠菌病的敏感性显着增加。为了开发“干嘴”的疗法，了解导致唾液分泌的过程在生理上以及这些机制如何改变病理状态非常重要。推动这一建议的总体原则是，可以使用实验研究和定量理论建模的协同组合来进一步了解我们对唾液腺生理学和病理学的理解，即单一方法都无法实现。在当前的建议中，将从实验数据中开发出多尺度流体分泌模型，该模型捕获了分子，细胞和腺体水平上流体流动所需的基本空间和时间机械特征。该方法将在模型预测和实验确定的参数和结果之间使用迭代测试的过程。该方法的功能是，该模型可用于定量解释和解释实验得出的数据，同时也建议进一步的实验，然后再进行预测其结果。然后，我们将使用来自SS患者的数据和疾病的小鼠模型对模型进行调整，首先研究SS中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，如何增加唾液流动。最后，我们将再次基于实验数据来调整该模型，以描述唾液腺irradiation在失去腺泡组织之前发生的唾液腺功能的降低。它设想该模型最终可能提出新的疗法来恢复唾液腺功能，这从传统的纯实验方法中很容易看出。