Open Collections

Rees, William

University of British Columbia

Inflammatory bowel disease (IBD) consists of two diseases, ulcerative colitis (UC) and Crohn’s disease (CD), both characterized by chronic inflammation in the gastrointestinal tract. Some of the strongest risk alleles, such as NOD2, ATG16L1, and XBP1, affect the functionality of intestinal epithelial cells (IECs). Recent evidence suggests that IECs from IBD patients have long lasting molecular rewiring of the intestinal cellular compartment, with inflammatory gene signatures persisting once inflammation is resolved. Due to the high metabolic burden of their physiologic requirements, IECs are prone to endoplasmic reticulum (ER) stress, which leads to the unfolded protein response (UPR)—a cellular protection pathway that restores translational homeostasis and removes irreversibly stressed cells. Since ER stress has been shown to contribute to the pathogenesis of IBD, I sought to understand how ER stress can drive anti-microbial immune responses, as well as its ability to alter intestinal stem cell (ISC) self-renewal and IEC de-differentiation to recover from ER stress induced damage. I found that ER stress alters the ability of IECs to respond to TLR5 agonist, bacterial flagellin, ultimately leading to the maturation of monocyte derived dendritic cells (moDCs). This mechanism would ultimately link IEC dysfunction to anti-commensal adaptive immunity, which is what is observed in IBD. I also found that IBD-derived IECs display persistent ER stress, which alters their ability to respond to FliC. To understand how ER stressed induced chronic damage alters IEC function, I created a new chronic damage model using repeated cycles of air-liquid interface (ALI) and submergence injury of human derived colon organoid monolayers (colonoids). Through repeated damage by submerging colonoids in culture media, I show significant changes in epithelial cell lineages and gene expression that correlate with epigenetic modifications similar to that described for inflammation-associated GI diseases such as IBD and cancer.

Text

2021-08-26

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/79463

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/