Grant: Project Grant

The name "inflammatory bowel diseases" (IBD) describes debilitating ailments of the intestine that affect a large number of Canadians and for which effective treatments are lacking. Intestinal inflammation can be caused by excessive inflammatory responses to the detection of danger signals. The identification of those pathways is essential to the understanding of the pathogenesis of IBD and to the discovery of novel therapeutic targets and strategies. Our laboratory focusses on an emerging class of danger signals named extracellular nucleotides. Our recent data show that the regulation of this pathway controls inflammation in a mouse model of IBD and that the blockade of the nucleotide receptor P2Y6 expressed at the luminal surface of the intestine fully prevents inflammation in this model. In this proposal, we aim to establish whether blocking P2Y6 by different means can consistently prevent inflammation in mouse models that mimic human colitis. We also propose experiments to decipher the mechanisms by which the activation of P2Y6 induces inflammation in both in vivo models in mice as well as in intestinal primary cell cultures with cells from both mouse and human. Indeed, we have access to fresh human pieces of intestines from control and from IBD patients. We have already observed that P2Y6 is also the dominant nucleotide receptor in the human cells. Our preliminary data make us anticipate that our work on this innovative hypothesis on the pathogenesis of IBD will reveal a novel pathway to be targeted for the treatment and improvement of IBD.