Grant: Project Grant

Colonic motility disorders, ranging from Irritable Bowel Syndrome (IBS) to chronic constipation and pseudo-obstruction, impose a heavy personal and economic burden affecting 7 million Canadians, with a health care cost of >$8 billion /year and >$8 billion/year in lost productivity. Children with chronic constipation experience depression and stunted education. Treatments are often not beneficial because we do not have a complete understanding of how motility is controlled and we do not know what is actually wrong with the colon of patients because we do not measure it. I propose inherently translational studies aimed at understanding mechanisms underlying colonic dysmotility, generating novel therapeutic approaches. My first aim is to understand the mechanisms by which the colon creates normal or abnormal motility with a focus on the critical role of interstitial cells of Cajal (ICC), the pacemaker cells of the gut that orchestrate most motor patterns. I am internationally recognized as a leader in this field and ICC abnormalities are the most common pathology finding in constipation. My second aim is to measure and understand motility dysfunction in patients, using 84-sensor high-resolution manometry. Parallel animal and human studies will allow me to identify optimal stimuli to be used in the assessment so that I can translate abnormal responses to stimuli into causes of dysmotility. My third aim is to understand pathophysiology. In animal models, and in patients through mucosal biopsies, I will reveal relationships between abnormal motility, abnormal bacterial composition and abnormal microbe-derived metabolites. As outcome I will obtain optimal diagnostic testing of colonic dysmotility in patients, a better understanding of the underlying pathophysiology to allow for better management of each patient to increase health-related quality of life. Elucidation of the nature of the dysmotility will allow the development of new treatments and reduce hospital costs.