Scientific Abstract

Proposal No. IBD-0047R
Principal Investigator: Steven C. Hebert, M.D.
Applicant Organization: Yale University (New Haven, Connecticut, U.S.A.)
Project Title: The colonic epithelial extracellular calcium(nutrient)-sensing receptor as a modulator of inflammatory bowel disease
Period of Award: March 1, 2003 - August 31, 2005

We hypothesize that activation of the colonic extracellular calcium(nutrient)-sensing receptor can prevent or reduce the severity of inflammatory bowel disease (IBD) by enhancing intestinal epithelial cell differentiation, improving the “barrier” function of the colon, and modulating the associated inflammatory response in IBD. In addition, activation of the calcium(nutrient)-sensing receptor in IBD may reduce the risk of development of colon cancer as a sequela of IBD.

Two types of receptor agonists will be used to enhance calcium(nutrient)-receptor activity. Calcium is the natural direct agonist of this receptor while the nutrients spermine (a polyamine) and tryptophan (an amino acid) act primarily as allosteric modifiers that increase the affinity of calcium on the receptor.

We will examine dietary activators of the calcium(nutrient)-sensing receptor in two different animal models of IBD and assess effects on the prevention of IBD and on treatment of IBD once it has been established. One animal model will be dextran-sulfate induced IBD in rats that provides an IBD-like pathology produced by an irritant or physical agent. In this model, disruption of the barrier function has been proposed as a mechanism for physical-agent induced IBD. The other model is the IL-10 deficient transgenic mouse. In this second model, alterations in both the intestinal barrier function and in the inflammatory responses to intestinal bacteria are thought to induce IBD. Thus, these two models complement each other and will provide a broad range of pathology for testing the potential beneficial effects of calcium and nutrient supplementation on IBD.