PROJECT SUMMARY/ABSTRACT This application proposes a five-year research career development program focused on innate lymphoid cells in the pathogenesis and individualized management of inflammatory bowel disease. The applicant, Siyan Cao, M.D., Ph.D., is an Instructor of Medicine at the Division of Gastroenterology at Washington University School of Medicine. Since completing gastroenterology fellowship, Dr. Cao has been working in the laboratory of Dr. Marco Colonna, where he discovered a novel role of endoplasmic reticulum stress in innate lymphoid cells. This proposal is an extension of the candidate’s previous work demonstrating IRE1α-XBP1-medicated stress pathway controls the activation of innate lymphoid cells in murine colitis and patients with inflammatory bowel disease. The proposed experiments will incorporate innate and mucosal immunology expertise from the candidate’s mentor, Dr. Marco Colonna, immune cell-epithelial cell interaction and microbiome experience from the candidate’s co-mentor, Dr. Rodney Newberry, RNA modification and degradation expertise from the candidate’s co-mentor, Dr. Nicholas Davidson, as well as expertise on intestinal organoids, tissue fibrosis, and translational/clinical studies from the candidate’s Research Advisory Committee members, Drs. Matthew Ciorba, Andreas Herrlich, and Parakkal Deepak. Together, the candidate will be uniquely positioned to acquire the knowledge and skill sets necessary to develop an independent research program investigating how cellular stress response orchestrates innate immunity in gut inflammation and open avenues for novel management in inflammatory bowel disease. Innate lymphoid cells reside on the mucosal surface and control tissue homeostasis. IRE1α-XBP1 is the regulatory hub of endoplasmic reticulum stress and implicated in inflammatory bowel disease in genome-wide association studies. IRE1α is highly expressed in innate lymphoid cells, although its role in those cells remains unknown. My studies have established that IRE1α-XBP1 controls the activation of innate lymphoid cells in both mouse colitis models and human inflammatory bowel disease. Using a comprehensive approach involving lymphocyte-organoid co-culture, genetic mouse models, and longitudinal patient cohorts, this proposal intends to elucidate the mechanistic role of IRE1α-XBP1 in innate lymphoid cells in intestinal inflammation, and how those pathways may become novel response biomarkers in inflammatory bowel disease. Ultimately, with the mentorship provided by Drs. Colonna, Newberry, Davidson, and the other Research Advisory Committee members, the knowledge and technical skills derived from the proposed experiments, and completion of the outlined career development plan, Dr. Cao will be well-prepared to establish an independent research program and is expected to be highly competitive for R01 funding.