Lay Summary

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

Increased dietary calcium intake has been shown in numerous animal studies and human clinical trials to enhance colonic epithelial cell differentiation and to reduce the risk of development of colonic adenomas.  We now know that extracellular calcium works through the activation of a specific receptor molecule on the surface of many types of cells.  Hebert (together with his colleague Dr. Ed Brown at Harvard) cloned this extracellular calcium (and nutrient)-sensing receptor (CaSR) from bovine parathyroid gland in 1993.  Subsequently, many laboratories have studied the biology of this novel receptor that senses extracellular calcium.  These studies established that the CaSR is expressed in many different cells and tissues and provides the major mechanism for cells detecting and responding to changes in extracellular calcium.  We recently showed that the CaSR is expressed on both outside surface and blood-sides of the colonic epithelial cells in rats, mice and humans (as well as in other parts of the intestine).

In addition to calcium, two other classes of nutrients have been identified as activators of the CaSR.  These nutrients are polyamines and amino acids.  These latter nutrients function by enhancing the ability of calcium to activate the CaSR.  Polyamines, like spermine, are required for normal postnatal gastrointestinal tract development and for maintenance of epithelial “health’ in the adult.  The polycationic nutrients are present in all cells and are derived by dietary intake, gut bacterial metabolism and mammalian cell production.

Recent work has suggested that dietary polyamine intake is particularly important in intestinal epithelial effects of polyamines.  A normal barrier function is important in reducing the disease-causing responses to irritant agents in the gut.  Thus, we hypothesize that activation of the colonic calcium(nutrient)-sensing receptor can prevent or reduce the severity of inflammatory bowel disease (IBD) by enhancing cell differentiation and the “barrier’ function in the intestine, and can reduce the risk of development of colon cancer as a sequela of IBD.