Scientific Abstract
Proposal No. IBD-0229
Principal Investigator: F. Gary Toback, M.D., Ph.D.
Applicant Organization: The University of Chicago (Illinois, U.S.A.)
Project Title: Assessment of therapeutic efficacy of a novel peptide in murine models of human IBD
Period of Award: April 1, 2008 – February 28, 2011
We have characterized several functions of a novel 18 kDa protein expressed in cells of the gastric antral mucosa that point to its efficacy as a new agent to treat inflammatory bowel disease (IBD). Antrum Mucosal Protein (AMP)-18, or gastrokine-1, and a synthetic peptide comprised of 21 amino acids derived from a central domain of the molecule (AMP peptide) are each cell protective, mitogenic, and motogenic. When given to mice with dextran sulfate sodium (DSS) - induced injury of the colonic epithelium, AMP peptide decreased the extent of mucosal erosions. Treatment with the peptide also reduced the clinical correlates of colonic injury by delaying the onset of bloody diarrhea, and protecting against weight loss and colon shortening. The cell protective effect of AMP peptide in mice and monolayer cultures of colonic epithelial cells appears to be mediated by its capacity to increase accumulation of tight junction (TJ) proteins, limit their loss during injury, and facilitate their assembly into new TJs following disruption of mucosal barrier structure and function.
The objective of this project is to determine if the beneficial effects of AMP peptide observed in the DSS model of colitis can be extended to additional murine models of human IBD, while asking if the effect of AMP peptide on TJs also alters intestinal permeability. Specifically, we will explore the potential of AMP peptide to act as a therapeutic agent in the following models of colitis: (i) mice given the hapten 2,4,6-trinitrobenzene-sulfonic acid (TNBS) which induces interleukin (IL)-12-mediated transmural inflammatory injury, (ii) IL-10 deficient animals exposed to the nonsteroidal anti-inflammatory drug piroxicam, and (iii) immunodeficient recombinase activating gene-2 knock-out (RAG-2 KO) mice depleted of regulatory T cells and then reconstituted with splenic CD45RBhigh CD4+ T cells. Our specific aims are to: (1) Determine if administration of AMP peptide acts as a therapeutic agent in three murine models of colitis that resemble human IBD, and (2) Determine whether AMP peptide affects intestinal permeability in vivo.
We anticipate that administration of AMP peptide will alter the course of colitis in the three murine models of human IBD, and thereby validate the potential clinical efficacy of a new agent that could be developed to treat IBD in the near future. The planned studies will also provide insight into how AMP peptide exerts its therapeutic effect in the injured colon by characterizing its actions on clinical and physiological targets including mediators of epithelial restitution and immune regulation, as well as intestinal permeability. By rapidly reestablishing the integrity of the intestinal mucosa, AMP peptide could restore barrier structure and function and prevent relapses and/or speed healing in patients with IBD.