Title: The role of epithelial barrier dysfunction in food anaphylaxis Project Summary/Abstract This K23 proposal comprises a five-year career development program designed to lead Charles F. Schuler IV, MD into independence as a physician scientist studying the confluence of food allergy, mucosal immunology, and epithelial barrier function. Dr. Schuler is an allergy and clinical immunology physician scientist with a long- term goal of improving the diagnosis and treatment of food allergy. This proposal builds on Dr. Schuler's experiences in laboratory and clinical research and leverages an existing human biorepository of samples from food allergy subjects undergoing oral food challenges, the gold standard of food allergy diagnosis. This proposal will proceed within the rich training environment at the University of Michigan Division of Allergy/Clinical Immunology and Mary H. Weiser Food Allergy Center, combining the co-mentorship of James R. Baker Jr, MD and Nicholas W. Lukacs, PhD with an outstanding advisory board of investigators. Dr. Schuler will follow a plan of formal coursework, professional development, and mentored research to successfully grow into an independent physician scientist. This mentored research includes 2 scientific Specific Aims Aim 1: Determine the role of barrier gene variants in FLG, SPINK5, and JAM-A in food allergy development. Aim 2: Examine the ability of net skin barrier measurements to predict or measure oral food challenge outcomes. Through completing these overarching Aims, Dr. Schuler will (1) evaluate how known and unknown variants in these key barrier genes contribute to food allergy; (2), identify additional barrier-related genes that lead to food anaphylaxis while seeking to construct a polygenic risk score for food allergy; (3), define the ability of trans- epidermal water loss to identify patients at risk of food anaphylaxis; and (4) develop trans-epidermal water loss as a real-time clinical measurement of anaphylaxis during food challenges. The programmatic line of research established here will lead to several opportunities for R01 proposals. In addition, the findings from this proposal will be validated using the Southeast Michigan Food Allergy Collaborative birth cohort, a large-scale biorepository that is now in development. This work can also lead to the development of non-invasive food allergy risk profiles to minimize the need for costly, cumbersome, and risky oral food challenges. Further, through this work Dr. Schuler will develop research skills broadly applicable to many different areas of allergy research. Thus, this K23 award will support and greatly accelerate the career development of Dr. Schuler into a successful, innovative, and independent investigator.