Grant: Operating Grant

Disorders of the intestinal tract, including inflammatory bowel disease (IBD) and, to a lesser extent, short bowel syndrome (SBS), are a significant cause of morbidity in Canada, with Canadians having the highest incidence of IBD in the world. Current treatment options for these patients are limited. However, the exciting recent development of the hormone glucagon-like peptide-2 (GLP-2), which both increases the size of the intestine and improves the ability of the intestine to prevent bacteria from reaching the blood stream, has resulted in successful phase 3 clinical trials for SBS and phase 2 trials for IBD. Furthermore, a long-acting GLP-2 analogue (Gattex) is pending FDA approval for use in patients with SBS. Despite the likelihood that GLP-2 will soon be in use as a novel therapeutic approach, its mechanism of action is not well understood. We have recently shown that GLP-2 action on the intestine requires a mediator, specifically another growth factor named insulin-like growth factor-1 (IGF-1), as well as the protein/receptor that carries out the actions of IGF-1 in the intestinal cells. We will continue these studies to examine the intracellular signals that link GLP-2 to intestinal growth and barrier function, as well as to identify the specific stem cells in the intestine that multiply in response to GLP-2, thereby increasing intestinal growth. The results of these studies will enhance our understanding of the pathways by which GLP-2 exerts beneficial effects on the intestine, and may lead to better therapeutic approaches to treat patients with intestinal disease.