Scientific Abstract

Proposal No. IBD-0188R
Principal Investigator:  Tor C. Savidge, Ph.D.
Applicant Organization:  University of Texas Medical Branch at Galveston (U.S.A.)
Project Title:  To examine the therapeutic potential of a novel mucosal barrier-inducing factor in the treatment of Crohn's disease
Period of Award:  March 1, 2007  – February 29, 2008

We have identified s-nitrosoglutathione as a novel homeostatic regulator of intestinal permeability that is actively produced and secreted by enteric glial cells. We propose that s-nitrosoglutathione regulates intestinal barrier function via transnitrosylation of epithelial tight-junction associated proteins. Transnitrosylation is a signaling mechanism involving post-translational modification analogous to protein phosphorylation and acetylation. We hypothesize that aberrant s-nitrosoglutathione homeostasis constitutes a disease mechanism in Crohn’s disease resulting in intestinal barrier dysfunction. A precedent for a role of s-nitrosoglutathione depletion in disease pathogenesis is known for asthma and amyotrophic lateral sclerosis. This view is also supported by our preliminary findings that s-nitrosoglutathione restores intestinal barrier function in biopsies from Crohn’s disease patients but not in control patients without inflammatory bowel disease. The identification of s-nitrosoglutathione as a glial-derived, small, soluble molecule that protects epithelial-barrier integrity represents a significant advance in the understanding of the cellular interactions that underlie intestinal barrier function. These findings may help in the development of novel therapies for pathologies, such as Crohn’s disease, that are associated with inflammatory barrier dysfunction.