DESCRIPTION (provided by applicant): Food allergy is a serious and common disorder within the U.S. and is thought to impact 1 in 4 families. The main approved therapy for food allergy is food avoidance; however, with the use of milk, eggs, peanuts and tree nuts in many foods in which their presence might not normally be anticipated, accidental and dangerous exposures are common. Recently, we identified a new mechanism of intestinal luminal soluble antigen sampling, which was mediated by goblet cell (GC) antigen passages (GAPs) 10. In preliminary studies, we identified a new pathway in the regulation of GAP formation and an important role for this pathway in atopic susceptible mice in both the development of clinical reactivity to foods and onset of an acute food allergic reaction. Our central hypothesis is that GAP-mediated intestinal antigen delivery primes for the "sensitized food allergic state" and stimulates clinical reactivity to foods. The Specific Aims outlined in this proposal will directly est the involvement of GAP formation in the facilitation of food antigen presentation, development of the sensitized food allergic state and clinical reactivity to foods. With respect to the expected outcomes, the studies proposed are expected to demonstrate that: Aim I) GAPs are the primary pathway of SI food antigen delivery to the immune system; Aim II) that cholinergic-induced GAPs promote the "sensitized food allergic state" in atopic susceptible" individual by enhancing the delivery of food antigens; and Aim III) MC-derived IL- 13 in close proximity to GCs induces GAP formation, thereby augmenting antigen delivery and onset of a food- induced anaphylactic reaction. Successful completion of the proposed studies will provide a new and substantive departure from our current understanding of the underlying mechanisms of intestinal luminal antigen sampling and development of clinical reactivity to foods and identify GAPs as an attractive target for the development of therapeutic intervention to prevent development of new food allergies.

PUBLIC HEALTH RELEVANCE: Food allergy affects ~2% of adults and 4% of children in the U.S. and has been rapidly increasing in prevalence. The medical and scientific communities have made significant advancements in identifying that combined genetic and environmental factors predispose to food allergy and anaphylaxis; however, the primary pathways involved in food antigen sampling and establishing of the pro-allergic environment that predisposes to clinical reactivity to foods remain unclear. Successful completion of the proposed studies will provide a new and substantive departure from our current understanding of the underlying mechanisms of intestinal food antigen sampling and development of food allergies and will identify new targets for the development of therapeutic interventions to prevent the development of new food allergies.