Grant: Operating Grant - PA: Inst of Nutrition, Metabolism and Diabetes -Bridge Funding

P2 receptors are actively involved in multiple inflammatory diseases with an inflammatory component, such as in Alzheimer's disease, Sjögren's syndrome, chronic pancreatitis and atherosclerosis. In the intestine, the activation of these receptors by extracellular nucleotides normally regulates the secretion and absorption of chlorine, sodium and potassium ions. However, the role of these receptors in the etiology of inflammatory bowel diseases is not known. Recently, we showed that the expression of P2Y2 and P2Y6 receptors was increased in the colonic epithelium of mice having colitis-like symptoms and in colonic tissues of patient suffering from Crohn's disease or ulcerative colitis. The exact cellular and molecular mechanisms regulating the expression of these receptors are not yet determined. We have, however, showed that the activation of P2Y6 receptor stimulates intestinal epithelial cells release of CXCL8 (IL-8), a chemokine involved in the recruitment of leukocytes. The overall objective of this research project is to unravel P2 receptors contribution to the epithelial cells inflammatory responses that could lead to the dysfunction of the intestinal mucosa. By combining various techniques of molecular and cellular biology and by the use of various animal models, we will delineate the exact roles of P2 receptors of intestinal epithelium in both a physiological context of mucosa homeostasis maintenance and in pathological conditions as found in intestinal inflammation. Hence, this proposed research project will serve as a stepping stone to establish the modalities of targeting P2Y6 receptor signaling as a therapeutic tool for the treatment of inflammatory bowel diseases.