Lay Summary

Proposal No. IBD-0164R
Principal Investigator:  Carsten Büning, M.D.
Applicant Organization:  Charité, Campus Mitte, Universitätsmedizin Berlin (Germany)
Project Title:  Genes involved in epithelial integrity as risk factors for inflammatory bowel disease?
Period of Award:  June 1, 2006 – November 30, 2007

Crohn’s disease (CD) is a multifactorial disorder with the following factors believed to play an important role in the development and course of the disease: an abnormal immune response, fecal bacteria entering the intestinal mucosal, environmental factors, genetic alterations and an increased intestinal permeability. Focusing on this increased intestinal permeability, this dysfunction in the epithelial integrity is believed to be involved in the invasion of fecal bacteria into the intestinal mucosa, initiating a chronic and devastating immune response.

The mechanisms leading to this disturbance of epithelial integrity remain to be elucidated. Interestingly, this increased intestinal permeability is also found in healthy relatives of CD patients. These observations suggest that this barrier dysfunction is induced by genetic mutations that are shared by CD patients and their healthy relatives. Up to now, no mutation has been identified to explain this disturbed epithelial barrier.

Within the last few years, the essential structures regulating the integrity of the intestinal epithelial cell have been found. Studies identified so-called tight junction proteins acting as a fence in order to maintain the internal environment. Occludin, claudin-1, claudin-4, and JAM-1 constitute the backbone of these tight junction proteins. If the function of these proteins alters, possibly due to a genetic defect, this could result in an abnormal invasion of antigens into the intestinal mucosa initiating an inflammatory response characteristic for CD.

Thus, we hypothesize that CD patients suffer from one or more mutations within these candidate genes (occludin, claudin-1, claudin-4, and JAM-1). We will investigate these candidate genes by sequencing in order to find mutations in our CD patients. If a mutation is found, we will determine whether this mutation is found in higher frequencies in CD patients compared to healthy controls.

If successful, our data might be helpful in the near future in several ways. They might be used to gain further insight into the pathophysiology of this intestinal barrier dysfunction. This might lead to the development of innovative and more specific therapies in order to restore this intestinal barrier. Furthermore, genotyping for these mutations might identify patients with a high risk of disease relapse and might help to predict the course of the disease better as well as the response to medical therapy. This would result in a more individualized therapy and would improve the lives of inflammatory bowel disease patients.