PROJECT SUMMARY/ABSTRACT This proposal describes a rigorous five-year training program leading to the career development of Dr. Lisa L. Korn as an independent physician scientist. The principal investigator is a physician scientist with a PhD in immunology who recently completed clinical fellowship training in rheumatology. Her career goal is to become an independent investigator working at the intersection of mucosal immunology and inflammatory diseases, studying how environmental influences in inflammatory disease are mediated by the intestinal immune system. She proposes to expand her training in gut physiology, the microbiome, and inflammation biology through an intensive training research experience under the mentorship of Dr. Ruslan Medzhitov, a pioneer and world leader in the complex biology of inflammation. In addition to intellectual mentoring and hands-on training in Dr. Medzhitov’s lab, she has designed a series of relevant didactic coursework and has carefully selected an advisory committee with extensive expertise both related to this project and in successfully mentoring physician- scientists. An outstanding scientific environment and extensive resources are provided by Yale University and its Departments of Medicine, Immunobiology, and section of Rheumatology. The research objective of this proposal is to study the interactions between nutrient signals and microbiota on eosinophil residency in the small intestine at steady state and in a mouse model of eosinophilic granulomatosis with polyangiitis (EGPA), an eosinophilic vasculitis that often involves the intestine. We found that small intestine eosinophils undergo a process of tissue adaption at steady state that involved transit of eosinophils up the crypt-villus axis with time, and changes in eosinophil morphology, surface marker expression, and transcriptional profile. The canonical eosinophil survival factor IL-5 was largely dispensable for eosinophil adaptation, while the vitamin A metabolite retinoic acid was required. Because small intestine eosinophils are most abundant in the part of the intestine that is most exposed to luminal nutrients, we asked whether these cells were further regulated by diet. Indeed, a high protein diet caused depletion of the villus-resident subset. Based on these findings, we hypothesize that coordinated environmentally derived signals regulate eosinophil small intestine tissue adaptation, and that they might affect intestinal eosinophilia in EGPA. Therefore, we propose to identify how retinoic acid and dietary protein impact the eosinophil small intestine adaptation process, to determine the impact of the localization of the intestinal microbiota on this process, and to identify mechanisms of intestinal eosinophilia in a mouse model of EGPA.