Final Report Summary - PIPE (Physiology of the Intestine: Proteases from the Epithelium)
We have generated data demonstrating that stimulated intestinal epithelial cells release proteolytic activity. We have identified several of these epithelium-derived proteases and we have investigated their role in mucosal physiology and pathophysiology.
We have identified a form of Elastase previously unknown in the intestinal epithelium. This form of Elastase plays a major pro-inflammatory role when overexpressed, and constitutes a new important target for the treatment of IBD.
We have identified a previously unknown protease of the Trypsin family, demonstrating its crucial role in Ulcerative colitis.
We have identified the effect of Trypsin-3, a well known member of the Trypsin family, in IBS and this has led to new R&D programs for the search of Trypsin-3 inhibitors.
We have demonstrated that an endogenous protease inhibitor released by the intestinal epithelium: Elafin, is protective and can be delivered using food-grade bacteria, to protect intestinal mucosa in models of IBD, but also of celiac disease and ischemia-reperfusion.
Further, we have studied the impact of epithelial proteases on enteric neuron signaling in a context of Irritable Bowel Syndrome (IBS) and we have demonstrated that proteases through the activation of Protease-Activated Receptors (PARs) are able to release polyunsaturated fatty acids that are able to activate a family of receptors (transcient receptor potential) that are playing a major role in visceral hypersensitivity associated with IBS.
Results raised from this study have already identified previously unknown actors of intestinal physiology and pathophysiology and of the neuro-epithelial crosstalks in the intestine. Other targets are currently investigated, and could lead to major knowledge on our understanding of mucosal physiology.