This proposal investigates the mechanisms by which retinoic acid, the active form of vitamin A suppresses production of inflammatory mediators that cause dry eye by monocyte derived cells in the conjunctiva. Dry eye is one of the most prevalent medical conditions affecting tens of millions in the US that decreases quality of life and productivity due to irritation and blurred vision. A hallmark of aqueous deficient dry eye is loss of conjunctival goblet cells. Goblet cells produce retinoic acid from vitamin A in tears. We hypothesize that retinoic acid signaling through the retinoid X receptor on monocytes suppresses desiccation stress induced production of IL-12 and IFN- , cytokines that cause goblet cell loss. Three specific aims are proposed to investigate this hypothesis in a mouse model of dry eye and in monocyte cell cultures. The proposed experiments investigate the novel suppressive activity of the retinoid X receptors on conjunctival monocytes and evaluate therapeutic activity of molecules that activate these receptors. These include drugs approved for other indications and dietary supplements. At the conclusion of this project, we will have a better understanding of the mechanisms by which retinoic acid maintains a healthy ocular surface and prevents development of dry eye. The benchmark accomplishments of this project will be a fundamental new understanding of the mechanisms that contribute to goblet cell loss and new approaches to utilize natural retinoid pathways prevent or treat dry eye disease.