Ulcerative colitis (UC) is a serious condition with the highest incidence and prevalence in Northern Europe and North America. Following industrialization and cultural implementation of a Westernized life style, a significant rise in UC has also been observed in Asia. UC is a long-term condition that results in colon and rectum inflammation, impacting the quality of life and potentially leading to colorectal cancer. The cause of UC is unknown. Basic research in genetically modified animal models coupled with high throughput sequencing technology to examine altered regulatory events because of disease has been of significant value in elucidating the pathophysiological factors involved in UC. Nuclear receptor corepressor 1 (NCoR1) interacts with a host of transcriptional factors that repress and transrepress families of genes that are closely associated with inflammatory events. The importance of intrinsic NCoR1 in intestinal homeostasis was first discovered in our laboratory when we generated intestinal epithelial cell (IEC) specific NCoR1 deletion mice (NCoR1?IEC) and identified the role of NCoR1 in regulating IEC proliferation and enterocyte maturation during neonatal development. When adult wild-type mice are treated with dextran sulfate sodium (DSS), an important experimental agent used in this discipline, the mice develop UC. In comparison to wild-type mice, NCoR1?IEC mice treated with DSS exhibit increased susceptibility to weight loss and colitis, heightened by a significant decrease in proliferative Ki67+ cells accentuated by a dramatic drop in mitotic Lgr5 gene expression. Furthermore, we discovered that IEC-NCoR1 deletion in nave (water exposure only) NCoR1?IEC mice leads to accelerated cell proliferation along with transcriptional inhibition of various antimicrobial peptides (AMPs), including Reg4, Ang4, and Itln1. In colon tissue, AMPs are produced by Paneth-like deep crypt secretory (DCS) cells, which are intimately coupled with mucin-producing goblet cells to form the first line of innate defense in protecting IECs and the intestinal stem cells (ISC) that reside at the bottom of the crypts. Therefore, we hypothesis that ?intestinal NCoR1 protects crypt cells through regulating the function of colonic secretory cells?. By utilizing both nave and DSS-treated NCoR1F/F and NCoR1?IEC mice, we will examine ISC proliferation, migration and apoptosis. We will also determine the impact on mucus thickness, goblet cell maturation, and regulation of DSC secretory markers. These studies will help us determine if altered AMPs and mucins in NCoR1?IEC mice lead to bacteria penetration and crypt cell apoptosis. In addition, global genomic studies will be initiated to identify molecules and pathways that are associated with the differentiation and maturation of goblet and DCS cells. Included in these pathways will be examination of the role played by IL-18, an important epithelial- derived cytokine involved in regulating goblet cell maturation which is repressed in IECs by NCoR1. We will determine the possibility that NCoR1 maintains intestinal homeostasis through regulating cytokine IL-18 signaling.
We will provide evidence that targeted deletion of the Nuclear receptor co-repressor-1 (NCoR1) in colonic tissue (NCoR1?IEC mice) will sensitize these mice to exhibit a higher susceptibility to chemical induced Ulcerative Colitis (UC). Studies are outlined using this novel animal model to characterize how IEC-NCoR1 deletion impacts on colonic secretory cells, which minimizes the protective function of mucins and antimicrobial peptides. The altered secretory events predispose NCoR1?IEC mice to inflammation, which serves as a pathological factor in UC initiation and development.
