The endoplasmic reticulum (ER) is responsible for the synthesis, folding and structural maturation of proteins. When protein-folding requirements exceed the processing capacity of the ER, misfolded and unfolded proteins accumulate in the ER lumen, leading to a condition termed ER stress.
ER stress results in the activation of a complex adaptive signaling pathway called the Unfolded Protein Response (UPR), which, in case of irremediable ER stress, can drive cells into apoptosis. Activation of all three branches of the UPR – namely IRE1/XBP1, ATF6 and PERK/ATF4/CHOP – is observed in a broad number of chronic disorders including inflammatory bowel disease (IBD). Whereas Kaser et al. (2008) as well as Niederreiter et al. (2013) describe that loss of the IRE1/XBP1 branch of the UPR in highly secretory epithelial cells result in spontaneous intestinal inflammation in mice, CHOP-deficient mice are even protected from DSS-induced colitis. Thus, a complex inter-crosstalk of the UPR pathways is assumed to contribute to disease development and progression. Here, we hypothesize that also other IBD risk genes might interfere with ER stress signaling, thereby regulating disease severity and/or progression.
We aim to investigate whether certain IBD risk genes as identified by Genome Wide Association Studies can function as modulators for ER stress pathways in the intestine. Specifically, we focus on elucidating the role of the IBD risk gene ORMDL3 on the XBP1 branch of the UPR in intestinal epithelial cells.
We will perform in vitro experiments with different intestinal cell lines in order to specify the relations between different UPR-related genes in response to various intrinsic and extrinsic stimuli. Moreover, we will establish ex vivo three-dimensional organoid cultures derived from mouse intestinal stem cells, which function as a model system for the gut and its associated cellular and molecular processes. Finally, a conditional mouse model deficient for both IBD risk genes XBP1 and ORMDL3 will be generated and its phenotype under basal conditions and in IBD colitis models will be closely monitored.
Arthur Kaser, Ann-Hwee Lee, Andre Franke et al. (2008): XBP1 Links ER Stress to Intestinal
Inflammation and Confers Genetic Risk for Human Inflammatory Bowel Disease. Cell 134, 743–756
Lukas Niederreiter, Teresa M.J. Fritz, Timon E. Adolph et al. (2013): ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells. J. Exp. Med. Vol. 210 No. 10, 2041-2056