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.

PUBLIC HEALTH RELEVANCE: The secretion of saliva is vitally important for a healthy mouth. Conditions that result in "dry-mouth" significantly decrease the quality of life of those afflicted. The goal of these studies is to use a combined experimental and theoretical modeling approach to understand how saliva is secreted and the processes that are altered in pathological states. This novel approach will ultimately be used to suggest novel therapies for "dry-mouth".