An official website of the United States government.

Official websites use .gov
A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS
A lock ( ) or https:// means you’ve safely connected to the .gov website. Share sensitive information only on official, secure websites.

Mast Cell-Mediated Intestinal Permeability

Investigators
Groschwitz, Katherine
Institutions
Cincinnati Children's Hospital Medical Center
Start date
2008
End date
2011
Objective
IgE/mast cell-mediated food allergies are serious and life-threatening immediate hypersensitivity reactions. Despite being highly prevalent and clinically important, there is a limited understanding of the molecular basis of oral antigen sensitization and susceptibility to food allergies. Recently, there has been significant interest in the role of impaired intestinal barrier function in the pathogenesis of a variety of Gl disorders, including food allergies and inflammatory bowel diseases.

Mast cells are key mediators in immediate hypersensitivity reactions and critical regulators of intestinal permeability. In preliminary studies, we have demonstrated an association between increased mast cells, mast cell chymase (murine mast cell protease-4 (mMCP-4)) and activated matrix metalloprotease-9 (MMP-9) with increased intestinal permeability.

The central hypothesis of this proposal is that mast cell-dependent intestinal permeability is mediated by mMCP- 4-dependent activation of MMP-9. We will test this hypothesis and accomplish the objectives of this grant application by pursuing the following specific aims: Aim #1: To determine the effect of mMCP-4 on intestinal permeability; and Aim #2: To delineate the role of mMCP-4-activated MMP-9 in intestinal permeability.

We will utilize in vitro, ex vivo and in vivo methods to examine the role of mMCP-4 and MMP-9 in intestinal permeability changes (transepithelial resistance and paracellular and transcellular marker flux). We will perform gelatin zymography to examine the role of mMCP-4 in intestinal MMP-9 activation. Furthermore, we will utilize novel transgenic and gene knockout mice, a murine model of oral antigen-induced food allergy and bone marrow transfer experiments to delineate the role of mast cell-derived mMCP-4 in the activation of MMP-9 and regulation of intestinal permeability.

Identification of a role for mast cells, mMCP-4 and MMP-9 in intestinal permeability will have a significant impact on our understanding of the mechanisms regulating intestinal permeability in health and disease, and implications for the development of therapeutic strategies for the prevention and treatment of food allergies and possibly other gastrointestinal diseases.

Relevance: This grant application will investigate the mechanisms regulating intestinal permeability, in particular the role of a protease secreted by mast cells. Understanding the regulatory mechanisms of intestinal permeability in both health and disease is required for effective treatment and prevention of food allergies and other gastrointestinal diseases.

More information
For additional information, including history, sub-projects, results and publications, if available, visit the Project Information web page at the National Institutes of Health Research Portfolio Online Reporting Tool (RePORTER) database.
Funding Source
Nat'l. Inst. of Diabetes and Digestive and Kidney Diseases
Project number
1F30DK082113-01
Categories
Parasites
Natural Toxins
Viruses and Prions
Bacterial Pathogens
Chemical Contaminants
Prevention and Control
Sanitation and Quality Standards