Scientific Abstract
Proposal No. IBD-0268R
Principal Investigator: Scott Smid, Ph.D.
Applicant Organization: The University of Adelaide (Australia)
Project Title: Functional role of the endogenous cannabinoid system in inflammatory bowel disease
Period of Award: February 1, 2010 – February 28, 2011
Peripheral cannabinoid (CB) receptors have been localized to both immune-competent cells and in various cell populations within the human gastrointestinal tract. The CB1 receptor subtype is located predominantly on enteric neurons, with CB2 receptors mainly located on immune cells. Endogenous ligands for the CB receptors include compounds such as anandamide and 2 arachidonylglycerol (2-AG). Such '‘endocannabinoids’ are synthesised from membrane lipid precursors and hydrolysed by fatty acid amide hydrolase (FAAH).
This study aims to explore the relationship between the endocannabinoid system and inflammation in the IBD-affected colon for the first time, by determining:
i) whether activation of the cannabinoid system is protective in human colitis. Does the activation of cannabinoid receptors or increasing endogenous cannabinoid levels exert a protective effect in colitis?
ii) if the endocannabinoid system is linked to cyclo-oxygenase-2 in the human colon. Can the novel endocannabinoid products of COX-2 metabolism, the ‘prostamides’, influence the inflammatory process and if so, are their effects mediated through pharmacologically distinct pathways?
The first part of this study will utilize specimens from healthy human resected bowel in tissue culture to generate an ex vivo model of acute colitis. This will be achieved by incubating colon specimens with key cytokines to induce inflammatory change and then comparing ‘colitis’ in the presence of a variety of cannabinoid, COX-2 and prostamide-selective ligands, in addition to measuring prostamide formation. This will enable us to determine, both directly and indirectly, the extent of inflammatory modulation of these systems in the human colon and the nature and extent of the interaction between the endocannabinoid system and COX-2.
In addition, we will source colonic biopsies from Crohn’s and ulcerative colitis-affected patients following colonoscopy and compare biochemical indices of endocannabinoid and COX expression and activity with designated healthy colonic tissue taken from patients undergoing bowel resections for colorectal cancer. Measurements of COX-2 and FAAH expression and activity will be compared against markers of inflammation, to determine the association between colitis and the endocannabinoid system.