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。该液体为口腔提供水合作用和润滑，而蛋白质含量则提供开始消化食物的酶，以及保护口腔和上胃肠道免受细菌和真菌感染的额外蛋白质。鉴于这些重要的生理功能，与自身免疫性疾病、干燥综合征（SS）相关的唾液腺功能低下以及头颈癌放射治疗导致的生活质量显着恶化；包括吞咽和咀嚼食物困难以及牙齿携带和口腔念珠菌病的易感性显着增加。为了开发“口干”的治疗方法，从根本上理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非常重要的。推动这一提议的总体原则是，实验研究和定量理论模型的协同组合可以用来进一步我们对唾液腺生理学和病理学的理解，这是任何一种单一方法都无法实现的。在当前的提案中，将根据实验数据开发液体分泌的多尺度模型，该模型捕获分子、细胞和腺体水平上液体流动所需的基本空间和时间机制特征。该方法将使用模型预测与实验确定的参数和结果之间的迭代测试过程。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，还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，然后使用该模型来预测和实验测试如何增加唾液流量。最后，我们将再次忠实地基于实验数据来调整该模型，以描述在腺泡组织丧失之前对唾液腺进行 g 照射后发生的唾液腺功能下降。预计该模型最终可能会提出恢复唾液腺功能的新疗法，而这从传统的纯实验方法中并不容易看出。