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: 8089441
• 负责人: A. JAMES R. SNEYD
• 金额: $ 73.83万
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8089441
• 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

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，美国高达20%的成年人患有口干症。这种慢性疾病的发病率非常高，在极端情况下会导致营养不良。产生足够唾液的能力下降与许多主观和客观的功能缺陷有关，包括口腔干燥的感觉（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（如白色念珠菌）的易感性增加。治疗往往只是部分有效，经常产生不良副作用，通常需要终身使用。改善这些治疗的重要的第一步是彻底了解参与分泌的分子途径。虽然我们对外分泌腺功能和调节的理解取得了实质性进展，但我们的知识仍然存在重大差距。特别是，我们还没有清晰地了解信号通路和效应分子之间的协同作用，以调节唾液腺的液体产生。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，这样的数学模型能够提供对复杂系统的行为如何依赖于其组成元素的行为的总体理解。首先，我们将开发单个腮腺腺泡和导管细胞的模型，并将这些模型偶联到单个腺泡和相关导管的原型分泌单位的大型模型中。然后，该模型将根据大量现有的实验结果进行验证和测试，并将用于开发进一步的实验，以测试有关唾液腺功能和调节的假设。特别是，我们将研究细胞间偶联如何影响唾液分泌，分泌如何依赖于各种离子通道的空间定位和功能，以及细胞内钙浓度的振荡如何影响唾液分泌。项目简介：唾液腺功能障碍是数百万人的一个问题，对他们的生活质量有重大影响。尽管存在一些治疗方法，但由于我们对唾液分泌究竟是如何控制的了解有限，改进治疗方法的发展受到阻碍。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，并利用该模型指导后续的实验。