Transcriptional Mechanisms that Catalyze Dysregulated Type 17 Mucosal Inflammation via Innate Lymphoid Cells

Chronic inflammatory diseases, such as inflammatory bowel disease, psoriatic arthritis, and lupus, impose a significant public health burden. Despite our understanding of type 17 immune responses, the mechanisms by which aberrant type 17 inflammation is triggered and sustained remain unclear. Given the critical role of group 3 innate lymphoid cells (ILC3s) in immune homeostasis, this project aims to define how ILC3s can cause sustained inflammation and identify the molecular pathways governing this dysregulation. The findings will provide fundamental insights into immune regulation, to advance understanding of immune-mediated diseases, and improve therapeutic strategies. Aim 1 will determine the impact of ILC3 abundance on tissue homeostasis and inflammation by investigating how ILC3s influence T cell numbers, function, and inflammatory programs, contributing to tissue homeostasis. Aim 2 will define the role of ZBTB transcription factors in ILC3 maintenance and type 17 inflammation by examining how they regulate ILC3 populations, modulating immune responses from a homeostatic type 17 program to a pathogenic inflammatory state. To achieve these aims, the project will leverage a physiologically relevant A20 knock-in mouse model, which develops spontaneous mucosal inflammation mimicking human disease. The study will integrate in vivo immune profiling, transcriptomic analysis, and chromatin mapping to uncover how ILC3s contribute to type 17 dysregulation. By elucidating how ILC3s and transcription factors drive inflammation, this project will uncover key epigenetic and immune regulatory mechanisms. Furthermore, these studies open up potentially new therapeutic targets for chronic inflammatory diseases. These findings will provide a foundation for developing novel interventions that restore immune balance/homeostasis and prevent pathogenic inflammation. Dr. Bowman is a clinical research fellow at the University of California, San Francisco. Prior research training has given him expertise in molecular, chromatin, and computational biology, and his clinical specialty is in gastrointestinal and hepatobiliary pathology. This application for a Mentored Clinical Scientist Research Career Development Award (K08) will combine all areas of his expertise with the immunobiology of ILCs in the context of mucosal inflammation. The proposed research and career plan will foster the intellectual and professional skills required for his establishment as a successful and independently funded physician-scientist. This plan includes mentorship by Dr. Averil Ma, a leading expert in intestinal immunology; scientific and career advisory by a multidisciplinary committee that includes leaders in the fields of innate lymphoid biology, computational biology of dysregulated immune networks, and the immunology of human diseases; coursework in immunobiology, biostatistics, and high-level bioinformatics; and professional development activities. This structured plan will provide Dr. Bowman with the necessary skills to marry his research in molecular immunobiology with his growing clinical expertise in gastrointestinal pathology. Project Number: 1K08AI196236-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Christopher Bowman | Institution: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, SAN FRANCISCO, CA | Award Amount: $201,744 | Activity Code: K08 | Study Section: Special Emphasis Panel[ZRG1 IIDA-T (80)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1K08AI19623601