The Mary H. Weiser Food Allergy Center and the closely associated Allergy and Clinical Immunology Division in Medicine are submitting this application for a CoFAR CRC center. The Weiser Center has developed strong programs in basic and clinical research in food allergy with over 20 faculty and $10M a year in external research funding. It performs its research in the Davidson Endowed Food Allergy Research Laboratories and through the University's clinical trials support Office (CTSO) its faculty perform clinical research and have participated in 13 of the most prominent trials of therapeutic development in food allergy. The Allergy Division's clinical operation includes 18 allergists that see over 6,000 unique patents per year (60/40% pediatrics-adult) with food allergy diagnoses. Our proposal under Subsection B involves a new diagnostic approach for food allergy. Transepidermal water loss (TEWL) provides a potential approach to monitor physiological allergic reactions to food during food challenges to avoid the induction of anaphylaxis. TEWL is an established measure of skin barrier permeability that quantifies water efflux from the epidermis (units are g/m2/h). In anaphylaxis, blood vessels dilate leading to heat and water loss, and recent data suggests that the extravasation of serum fluid and proteins is proportional to the severity of allergic reaction. Our group has shown that real-time TEWL rises prior to clinical evidence of anaphylaxis and correlates with biochemical markers of anaphylaxis. We hypothesize that TEWL-based stopping rules can predict OFC reactions for any food and reduce the rate of OFC anaphylaxis while improving OFC accuracy. We propose to initiate a multi-site clinical trial in a diverse cohort with OFC for the major food allergens in the US to definitively assess TEWL's capacity to predict anaphylaxis during OFCs. Finally, under Subsection C we will examine the relationship between food allergy and atopic dermatitis, two disorders that share numerous genetic and environmental risk factors as well as pathogenic features. While the importance of epithelial barrier dysfunction in food allergy pathogenesis has been recognized, genome-wide association studies (GWAS) have identified only a limited number of food allergy risk genes, and our understanding of the shared genetic underpinnings of these disorders remains limited. We propose to access multiple genomic databases (covering >30,000,000 variants and >750,000 distinct individuals) to test the hypothesis that a shared permissive genetic signature involving epithelial skin barrier-related genes underpins atopic dermatitis and food allergy predisposition. We propose to 1) Deploy the above datasets for GWAS analyses in atopic dermatitis and food allergy separately followed by a trans-disease meta-analysis with Mendelian Randomization studies to define novel risk loci for each disorder and the directionality of each SNP's effects between diseases; 2) Interrogate known and newl...