Grant: Project Grant

Ulcerative colitis (UC) is a common inflammatory bowel disease (IBD) typified by recurring episodes of inflammation and tissue injury in the mucosal layers of the colon. The SOCS1 protein is an inhibitor of cytokine signaling affecting intestinal inflammation in a cell-specific manner, but its role in the intestinal epithelial cells (IEC) is unknown. This research team previously showed that mice with Socs1 gene deletion in IECs (Socs1dIEC) develop fatal UC at about seven months of age. Comparison of Socs1dIEC mice who displayed UC with those younger having no clinical sign of intestinal disease support a model whereby SOCS1 deficit in IECs may trigger UC by causing IEC secretory defects. This would lead to aberrant mucosal immune response to commensal bacterial invasion, where IEC hypersensitivity to death-inducing molecules produced by pathogenic immune cells may account for erosion of the colon epithelium. To tackle these postulates, we will define IEC-microbial-immune dynamic changes in the intestine of Socs1dIEC mouse cohorts (paired with WT littermates) featuring discrete disease evolution by performing functional, histologic and biochemical analyses. We will test whether disruption of the intestinal barrier integrity, bacterial invasion or mucosal infiltration of specific immune cell subsets cause UC or affect its evolution in Socs1dIEC mice. We will define IEC-intrinsic SOCS1 molecular pathways by global profiling changes in protein and gene abundance in IECs driven by SOCS1-deficiency, while SOCS1-regulated biological processes in mouse intestinal organoid culture systems. The cause of IBD is unknown but their pathogenesis is linked with aberrant immune response to the commensal microbiota. Insights of the mechanisms by which SOCS1 in IECs limits colitis may shed light on novel causes of IBD and identify cell targets for designing tailored new therapies to fight these diseases. Thus, our work would impact future diagnosis or treatments for IBD patients.