We have discovered a novel single-gene defect in patients with pediatric IBD, setting the stage for new molecular and cellular discoveries to dissect biology stemming from human disease. Here, we will pursue two aims that will open new doors by leveraging the strength of preclinical models to uncover mechanisms by which the gene we identified in patients orchestrates immune responses and inflammation in the gastrointestinal tract. Specifically, we will assess roles for this gene in regulating production of the inflammatory IL-1 cytokine and begin to dissect interplay between immune cells lacking this gene and bacteria in the intestine. Since our work begins with patients, our findings will be directly translatable between humans and mice and will advance our unbiased gene discovery to mechanistic insights more broadly relevant for mapping immune interactions relevant for the larger IBD community. Together, these aims address innovative new hypotheses and will advance the mission of the Kenneth Rainin Foundation by enabling transformative IBD discoveries rooted in human biology and advanced with powerful modeling approaches.