Abstract Secretion from the major salivary glands provides both fluid that hydrates and lubricates the oral cavity and proteins that begin to digest food. In addition, factors are also present in saliva that protect the oral cavity and upper gastrointestinal tract from bacterial and fungal assault. Hypo-function (xerostomia) of the salivary glands resulting in a reduction of fluid flow leads to a severe deterioration in the quality of life and is associated with the auto-immune disease, Sjögren’s syndrome (SS) and following radiotherapy for head and neck cancers. Xerostomia results in difficulty swallowing and chewing food and a marked increase in dental carries and susceptibility to oral candidiasis. To develop therapy for xerostomia or “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 isolation. In the current proposal, we will build on our model by incorporating the impact of communication between cells through junctional complexes in the acinus. In addition, we will generate a 3D model of salivary duct function and integrate this information into the acinus model to generate an anatomically correct 3D model of salivary gland fluid secretion. 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 investigate the mechanism whereby alterations in inositol 1,4,5-trisphosphate receptor function as a consequence of proteolysis that occurs early in models of SS, impact global Ca2+ signaling. Based on this information, we will adapt the salivary gland model to investigate the impact of these events on fluid secretion. Finally, we plan to use the model to understand and experimentally test how introduction of aquaporin proteins into duct cells following gamma-irradiation, leads to ion secretion and fluid flow from cells which normally reabsorb ions and thus cannot support water movement. Based on model predictions, we will test experimentally means to further enhance fluid flow from duct cells. It is 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.