Final Report Summary - PIPE (Physiology of the Intestine: Proteases from the Epithelium)
In several gastrointestinal diseases such as irritable bowel syndrome (IBS) or inflammatory bowel diseases (IBD), proteolytic homeostasis is disrupted. This disruption has an important impact on the pathophysiology of those diseases. We hypothesized that intestinal epithelial cells are major regulators of this homeostasis by secreting proteases and protease inhibitors, thereby interfering with gut biological functions and enteric neuron biology.
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.
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.