Project 457596

In Canada, Inflammatory bowel disease (IBD), a kind of inflammation in the small or large intestines, affected over 260000 Canadians. More importantly, it cost over 2.1 billion to the health care systems annually. It has been proved, white blood cells (WBC) play key roles in creating inflammation and IBD by releasing different small proteins such as IL-8, promoting the migration of inflammatory WBC. Therefore, We have made the novel observation that some chromosome components, called extracellular nucleotides (ENs), regulate IL-8 secretion in human WBC. Blocking either the action of extracellular nucleotides or their receptors P2Y6 both prevented IL-8 expression and secretion, as well as WBC migration to the inflammatory site. ENs (ATP, ADP, UTP and UDP) are secreted in large amounts by injured and activated cells, especially at sites of inflammation. The signaling and functions induced by ENs in WBC activation is a newly emerging field. ENs regulate a variety of functions and act through a number of specific receptors such as P2Y6. The concentration of ENs is tightly regulated by the expression of cell surface enzymes. We have discovered the first member of a new family of such enzymes that break down these molecules at the surface of macrophages and neutrophils (kind of WBC). We engineered mice deficient (MD) in this novel enzyme, named NTPDase1. These mice represent a powerful tool to explore the function of nucleotides in inflammation. Our preliminary data suggest the involvement of two nucleotides (P2-) receptors in cell migration, and we have obtained MD in the expression of these receptors from a collaborator. In this project, using MD in these three cell surface proteins, together with cellular and in vivo models, we will elucidate the function of nucleotide signaling in inflammation. We anticipate that our studies will lead to the identification of novel therapeutic targets that will help understand and treat inflammatory diseases such as IBD.