Grant: CAG/CCFC/CIHR Summer Studentship for Research in Gastroenterology

Crohn's disease (CD) is a chronic inflammatory disorder affecting the digestive tract (most commonly the terminal ileum) and characterized by important ulcerations and tissue damage, which result, among other symptoms, in severe abdominal pain, bloody diarrhea and weight loss. CD occurrence has increased steadily during the past century, especially in developed countries, but its etiology remains poorly understood. Among occidental countries, it must be noted that CD is very prevalent in Canada in general, and even more so in some specific areas such as Nova Scotia. Therefore, CD represents a serious and expanding medical threat for Canadian, and this disease has a considerable human and economical cost for the country. Therefore, research aiming at understanding the causes and etiology of CD will have an important impact on the health of Canadians and will be beneficial for the health care system in general. As stated above, the etiology of CD remains enigmatic, but it is clear that a dysregulation of the relationship with the intestinal microflora plays a crucial role in the development of the disease, and genetic factors also increase the susceptibility to this pathology. In particular, Nod2 has been identified in 2001 as the first susceptibility gene for CD. A few months later, we demonstrated that Nod2 was a crucial sentinel molecule expressed mainly in macrophages, and was responsible for the detection of peptidoglycan, a bacterial-derived cell wall molecule. Today, it remains unclear how mutations in Nod2 contribute to the increased susceptibility to CD. Our working hypothesis for this proposal is that these mutations, and in particular the Nod2 frameshift mutation at position 1007 (Nod2fs, the most common Nod2 variant associated with CD), may alter the expression of Nod2 in macrophages. Surprisingly, this simple hypothesis has never been tested experimentally, and forms the basis of this proposal.