Scientific Abstract

Proposal No. IBD-0222R
Principal Investigator:  Mathias Chamaillard, Ph.D.
Applicant Organization:  Institut Pasteur de Lille (France)
Project Title:  Role of a c-type lectin on NOD2 signaling in Crohn's disease
Period of Award:  April 1, 2008 – February 28, 2011

In IBD, serological and intestinal expression of the pancreatitis-associated protein (PAP) is increased. Similarly in mice, PAP is overexpressed by enterocytes in the course of acute and chronic colitis but not in the recovery phase of colitis. PAP is a soluble calcium-dependent C-type-lectin, which is prominently expressed by enterocytes upon recognition of the microbiota. PAP is a regulatory molecule involved in inflammation and tissue repair, but also in bacterial proliferation by binding to bacterial peptidoglycan (a NOD2 agonist), indicating that PAP might represent a negative regulator of NOD2 signaling. Our preliminary results indicate that the CD-associated NOD2 (R702W, G908R, 1007fs) and TLR4 (A299G) mutations correlate with increased serological titers of PAP, suggesting its use as a predictor of disease activity. Accordingly, chemically-induced acute colitis was markedly attenuated in mice deficient for PAP. These results suggest us that the impaired barrier function (e.g., NOD2 mutations) might lead to sustained microbial-induced PAP expression (i.e., mainly through engagement of TLRs signaling by commensals) leading to abnormal intestinal innate immune and tissue repair responses.

Our results support the notion that PAP might influence IBD pathogenesis and indicate that PAP might represent a therapeutical target in IBD. However, the underlying pathophysiological mechanism linking PAP to the natural clinical course of the disease remains poorly understood. The studies outlined in this proposal are designed to have an impact on biomedical research by i) assessing the clinical value of PAP testing in predicting clinical relapse in IBD patients, and ii) determining the immunological basis of the role of PAP in the gut epithelial response against chronic colitis and CD-related bacteria in mice. Taken as a whole, the proposed work may provide a non-invasive ‘biosensor’ of clinical relapse of disease activity and innovative therapeutic strategies aimed at targeting PAP.