Wednesday, April 2, 2025
4/2/2025
Impact of AIM2 on Intestinal Stem Cell Differentiation During Inflammation - PROJECT SUMMARY/ABSTRACT The mammalian intestine represents one of the most complex and immunologically-relevant organ systems. This is due to its heterogenous mixture of epithelial cells that constantly interact with the trillions of microbes comprising the intestinal microbiota and the underlying immune cells that inhabit the lamina propria. It is well accepted that host-microbiota interactions at these mucosal sites are critical to localized and systemic immune development, and disruptions in these interactions are associated with several chronic inflammatory diseases like inflammatory bowel diseases (IBD). Yet, there is still much we do not understand about how the communication networks between microbes, epithelial barriers and immune cells dictate the balance between productive immunity and immune tolerance. Several mammalian pattern recognition receptors (PRRs) expressed by immune cells and intestinal epithelial cells have been implicated in linking microbe-epithelial- immune interactions during the regulation of IBD, with mutations in NOD2 being heavily associated with human Crohn’s disease. Additional PRRs provide protective effects during animal models of experimental IBD, including members of the NOD-like receptors (NLRs) and related DNA sensor Absent in Melanoma 2 (AIM2) through formation of a multi-protein complex called the “inflammasome” and other non-inflammasome-mediated functions. We have evidence that AIM2 is also critical to the development of specialized intestinal epithelial cells called tuft cells, which initiate type 2 innate immunity in the small intestine. Tuft cell-driven type 2 immunity can counteract the pathological Th1/17 immune responses that are hallmarks of many forms of IBD. However, the molecular and cellular processes by which AIM2 accomplish this function is completely unknown. These questions will be addressed using tissue-specific animals models of AIM2 deletion, intestinal epithelial organoid models and experimental models of small intestine inflammation. The successful completion of this project will lead to the identification of novel innate immune targets, cellular signaling pathways and microbial triggers that can redirect immune activation, thus revealing new intervention points to promote IBD resolution.
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