AGR2 is a pathogenic driver of inflammatory bowel disease – PDI2

The project seeks to show the importance of neutralizing the extracellular action of the AGR2 protein (eAGR2) in the pathophysiology of inflammatory intestinal diseases (IBD) through the use of a specific antibody developed by French Biotech Thabor Therapeutics. AGR2 is an endoplasmic reticulum-resident protein that belongs to the protein disulfide isomerase family and is exclusively expressed in mucosecreting epithelial cells where it participates in the quality control of mucins. Under pathological conditions, AGR2 is abnormally secreted and acquires gains of function. We and other teams have recently shown the instrumental role of AGR2 in the development of IBD and its ability to induce inflammatory and fibrosing responses when secreted into the extracellular environment. We hypothesize that the neutralization of eAGR2 by a specific antibody represents an effective leverage to limit its deleterious effects and thus restore intestinal homeostasis.
The objectives of the study are to
1- decipher the mode of action of the eAGR2 protein on the main cell types involved in IBD by identifying the partners/receptors interacting with eAGR2 using a proximity biotinylation approach coupled with mass spectrometry,
2- to evaluate the impact of AGR2 secretion on the gastrointestinal phenotype using a transgenic mouse model developed in the laboratory overexpressing in a conditional and targeted manner (recombinase dependent on the Villin promoter) the WT or mutant form of AGR2 (WT or E60A secreted form).
3- To evaluate the tissue and circulating expression of AGR2 in the fluids (serum, stools, urine) of patients with IBD and to correlate its expression with the severity of IBD.

The project brings together three partners who have already collaborated and who have complementary skills for the project