Lay Summary

Proposal No.   IBD-0076
Principal Investigator:  Dirk Föll, M.D.
Applicant Organization:  University Hospital of Münster (Germany)
Project Title: The role of the receptor for advanced glycation end products (RAGE) and its ligand S100A12 (EN-RAGE) in chronic inflammatory bowel disease
Period of Award:  November 1, 2003 – June 30, 2006

The underlying factors causing chronic inflammatory bowel disease (IBD) are still poorly understood. However, we do know that white blood cells invade bowel tissue and contribute to an excessive inflammation during IBD. In order to leave the blood stream and invade the bowel, inflammatory cells attach to cells of intestinal blood vessels and finally pass this cell lining that normally functions as a barrier between tissue and the blood stream. One factor contributing to this interaction between white blood cells and the blood vessel wall is a protein called S100A12 (or calgranulin C; EN-RAGE) that is secreted by inflammatory cells.

The aim of our studies is to identify serum markers that help assessing the disease activity of chronic IBD. Correct assessment of the activity of inflammation in individual patients is important to guide therapy, which has to balance the risks of under- and over-treatment. We have identified that S100A12 - produced and released by the most abundant human white blood cells called neutrophils - is a potential marker for the disease activity of IBD. We have demonstrated that S100A12 is clearly elevated in the blood of patients with active IBD. In addition, we found that S100A12 decreased to almost normal in times when the disease was completely inactive. We will investigate the relevance of S100A12 as a prognostic marker for the risk of individual patients to develop long-term complications or reactivations.

The primary clinical benefit of our studies will thus be the generation of more sophisticated diagnostic markers for IBD. The correct assessment of the disease activity will help to guide treatment. In the future, S100A12 may also serve as a new target for therapeutic interventions. This protein initiates inflammation via cell surface receptors found in small blood vessels. To date, the involved mechanisms are not completely understood. We will investigate if the effects of S100A12 directly mediate inflammation by changing the function of small blood vessels. This may lead to new insights into the underlying mechanisms causing IBD. The binding of S100A12 to its receptor seems to be important, and this interaction might be blocked by future drugs that can be used to treat patients with chronic IBD.