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：
8274335
负责人：
A. JAMES R. SNEYD
金额：
$ 73.46万
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 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8274335
关键词：
Ablation Accounting Acinar Cell Acinus organ component Address Adult Adverse effects Affect American Animals Apical Behavior Calcium Calcium Signaling Calcium-Activated Potassium Channel Candida albicans Cells Chronic Complex Computer Simulation Coupling Data Deglutition Dental caries Dependence Dependency Development Dryness Duct (organ) structure Electrolytes Elements Esthesia Exocrine Glands Experimental Models Fluids and Secretions Functional disorder Generations Genes Goals Heterogeneity Human Indium Individual Investigation Ion Channel Knock-out Knowledge Lead Life Liquid substance Location Mastication Measurable Measures Membrane Potentials Modeling Molecular Morbidity - disease rate Mus Opportunistic Infections Oral Parotid Gland Pathway interactions Phase Physiological Physiology Positioning Attribute Potassium Channel Predisposition Process Production Property Quality of life Reaction Regulation Research Personnel Role Saliva Salivary Salivary Glands Salivary duct structure Signal Pathway Simulate Structure System Testing Time Variant Water Work Xerostomia absorption basolateral membrane improved mathematical model model design research study saliva composition saliva secretion secretion process synergism tool voltage

项目摘要

DESCRIPTION (provided by applicant): The quality of life for millions of Americans is adversely affected by salivary gland dysfunction. It is estimated that up to 20% of adults in the US will suffer from xerostomia. The morbidity of this chronic condition is very high, leading in extreme cases to malnourishment. The decreased ability to produce adequate levels of saliva has been associated with numerous subjective and objective functional deficits including the sensation of oral dryness (xerostomia); difficulty with speaking, mastication and swallowing; and an increased susceptibility to caries development and opportunistic infections (e.g., Candida albicans). Treatments are often only partially effective, frequently producing adverse side-effects and usually requiring life-long use. An important first step in improving these treatments is a thorough understanding of the molecular pathways involved in secretion. While substantial advances have been made in our understanding of exocrine gland function and regulation, there remain significant gaps in our knowledge. In particular, we have not yet achieved a clear picture of the synergisms required among signaling pathways and effector molecules to modulate fluid production from salivary glands. We shall address this problem using a multi-scale mathematical and computational model. Unlike purely experimental work, such mathematical models are able to provide an overall understanding of how the behavior of a complex system depends on the behaviors of its constituent elements. Initially we shall develop models of individual parotid acinar and duct cells, and couple these models into a large-scale model of a prototypical secretory unit of a single acinus and associated duct. The model will then be validated and tested against a large set of existing experimental results, and will be used to develop further experiments to test hypotheses about salivary gland function and regulation. In particular, we will examine how intercellular coupling affects salivary secretion, how secretion depends on the spatial positioning and functioning of the various ion channels, and how oscillations in the intracellular calcium concentration affect saliva secretion. Project Narrative: Salivary gland dysfunction is a problem for millions of people, with a significant impact on their quality of life. Although some treatments exist, development of improved therapies is hampered by our limited understanding of exactly how saliva secretion is controlled. We shall combine experimental investigations with a computational model to study the mechanisms of saliva secretion and control, and use this model to guide additional experiments.

描述（由申请人提供）：数百万美国人的生活质量受到唾液腺功能障碍的不利影响。据估计，美国多达 20% 的成年人患有口干症。这种慢性病的发病率非常高，在极端情况下会导致营养不良。产生足够唾液水平的能力下降与许多主观和客观功能缺陷有关，包括口腔干燥感（口干症）；说话、咀嚼和吞咽困难；以及对龋齿发展和机会性感染（例如白色念珠菌）的易感性增加。治疗通常只能部分有效，经常产生不良副作用，并且通常需要终生使用。改进这些治疗的重要的第一步是彻底了解分泌所涉及的分子途径。尽管我们对外分泌腺功能和调节的理解已经取得了实质性进展，但我们的知识仍然存在巨大差距。特别是，我们还没有清楚地了解信号通路和效应分子之间调节唾液腺分泌液所需的协同作用。我们将使用多尺度数学和计算模型来解决这个问题。与纯粹的实验工作不同，此类数学模型能够全面了解复杂系统的行为如何取决于其组成元素的行为。最初，我们将开发单个腮腺腺泡和导管细胞的模型，并将这些模型耦合到单个腺泡和相关导管的原型分泌单元的大规模模型中。然后，该模型将根据大量现有实验结果进行验证和测试，并将用于开发进一步的实验来测试有关唾液腺功能和调节的假设。特别是，我们将研究细胞间耦合如何影响唾液分泌，分泌如何取决于各种离子通道的空间定位和功能，以及细胞内钙浓度的波动如何影响唾液分泌。项目叙述：唾液腺功能障碍是数百万人面临的问题，对他们的生活质量产生重大影响。尽管存在一些治疗方法，但由于我们对唾液分泌的确切控制方式了解有限，因此阻碍了改进疗法的发展。我们将实验研究与计算模型相结合，研究唾液分泌和控制的机制，并使用该模型来指导其他实验。