Project Summary Epithelial cells are the first line of defense as they interface with the environment and initiate the response to environmental triggers. Our AADCRC is focused on elucidating the mechanisms by which epithelial cells contribute to the pathogenesis of allergic disorders. We found that while some epithelial genes are associated with tissue-specific disease, others are associated with specific combinations of disease and may contribute to disease progression from one end-organ to another. It is known that allergic disorders show substantial lifetime comorbidity. The “atopic march” concept has served as a guiding principle in our field, however, it has become evident that only very small proportion of children follow the traditional atopic march. While early-life AD remains a major risk factor for the development of atopic disease, there is significant heterogeneity in presentation of the atopic march including the timing and organ(s) affected. The atopic march needs to be revised to include this heterogeneity and incorporate the pathogenesis of the various combinations of the atopic march. Our Center is designed to help fill this critical knowledge gap. In the last cycle of funding, we built the first US early-life prospective longitudinal cohort of AD (Mechanisms of Progression of Atopic Dermatitis to Asthma in Children, MPAACH) and conducted mechanistic studies to identify epithelial pathways that promote allergic inflammation and disease. Our collective preliminary data implicate novel epithelial pathways as key drivers of allergic disease persistence in a given tissue as well as progression from one tissue to another. Herein, we will determine how these pathways act to promote the development, persistence, and progression of allergic and inflammatory diseases. Further, the atopic march needs to be revised to include non-White children. The vast majority of studies that served as the foundation for the atopic march principle were conducted in White populations, and our data reveal marked racial differences in the current atopic march concept. MPAACH is comprised of 65% Black children and was designed to help fill this critical need. The overarching hypothesis of this proposal is that homeostatic mechanisms at epithelial surfaces, upon dysregulation, promote allergic inflammation and contribute to the persistence, progression, remission and resolution of allergic disease(s). This hypothesis will be tested by three integrated and synergistic projects focused on epithelial cell biology that combine epidemiologic, basic, and translational research approaches to study multiple end-organs involved in allergic responses. Integration of data across projects by the Data Integration and Analysis Core (DIAC) will provide novel insights into a key unanswered question in the allergy field: Why is allergic inflammation restricted to one tissue in some cases, while it progresses to involve additional tissues in other individuals? Identification ...