Tuft cell heterogeneity in function, lineage, and structure in ileal inflammatory disease

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PROJECT SUMMARY/ABSTRACT Inflammatory bowel disease (IBD), such as Crohn’s disease (CD) and ulcerative colitis (UC), is a complex group of intestinal disorders that results in injury to the epithelium exposing the host to the luminal microbes. Tuft cells have recently been identified as a responder to the microbiome, where they can secrete damage-restitution molecules such as prostaglandins. Furthermore, our lab has successfully demonstrated that tuft cells promote the restoration of intestinal architecture in ileal inflammatory disease. In this supplement, we propose innovative experimental and computational approaches to decipher the effector molecules downstream of tuft cells that modulate inflammation. We will use mouse models where of tuft cell ablation and tuft cell specific gene knockout to determine whether prostaglandin production from tuft cells is responsible for their immunomodulatory effects. The epithelial and microenvironmental mechanisms responsible for these changes will be assayed by single-cell sequencing and multiplex immunofluorescence. Through our findings, we aim to make significant contributions to the current understanding of tuft cell biology and inflammation in the intestine. Ultimately, this research will allow us to better understand where tuft cells act in IBD and expand the pool of targets in this complex, multifactorial disease.