ABSTRACT Sjögren's disease is an autoimmune condition characterized by chronic inflammation and diminished secretory function of the salivary glands. Although extensive investigation has been done to understand it, causes of and effective treatments for the disease are still unknown. Given the high degree of need and the limitations of current therapies, development of novel treatments to decrease inflammation and restore salivary gland secretory function is essential. Previous studies demonstrated that a treatment with aspirin-triggered RvD1 and dexamethasone (AT-RvD1/DEX) reverses Sjögren's disease-like features in NOD/ShiLtJ mice at disease onset but the utility of this treatment is currently limited because the minimum effective dosage has yet to be established. Specifically, although AT-RvD1 has no known side effects, its relatively high cost could limit affordability. More importantly, DEX has been demonstrated to have significant side effects that can be expected to impede long-term use. By determining AT-RvD1/DEX biodistribution using mathematical modeling and thus defining the optimal (i.e., minimum effective) treatment dose, it is possible to manage the issues presented by both drugs and in so doing produce a cost-effective and clinically safe treatment option to mitigate symptoms associated with Sjögren's disease. To that end, it is hypothesized that systemic delivery of AT-RvD1/DEX will restore salivary gland secretory function in Sjögren's disease. Aim 1 will reduce AT-RvD1/DEX doses to their minimum effective levels, while Aim 2 will explore mechanisms by which AT-RvD1/DEX treatment outcomes are achieved and Aim 3 will apply AT-RvD1/DEX treatment to humanized systems.