Crohn's disease is a common illness of the gastrointestinal tract with a prevalence of approximately 0.1-0.2% in many developed countries; it affects approximately half a million Americans. It had been postulated that genetic mechanisms contribute to the pathogenesis of Crohn's disease. The recent finding that mutations of the Nod2 gene are observed in Crohn's disease patients at a high frequency has been one of the great successes of molecular medicine in the inflammatory bowel disease (IBD) field. However this finding by itself cannot make possible prevention or treatment of Crohn's disease since we do not know the mechanism whereby mutation of Nod2 gene leads to susceptibility to the disease. Recently, we found that Nod2 signaling requires the kinase, Rip2/Rick using Rip2 deficient mice. Our goal in this proposal is to elucidate IBD disease mechanisms by using genetically manipulated mice. There are two conceivable scenarios through which mutation of Nod2 could play a role in disease pathogenesis, namely loss or gain of function of Nod2. At this stage both mechanisms are possible. Therefore, by using two different strains of mice, Nod2 deficient mice and Nod2 transgenic mice, we will address this question and try to reveal the underlying mechanisms whereby Nod2 mutation contributes to Crohn's disease. Furthermore, by using mice in which Rip2, the kinase downstream of Nod2, is deficient, we will try to reveal if the IBD pathology caused by Nod2 mutation is dependent on Rip2. ? ?
| Frias, Amena H; Jones, Rheinallt M; Fifadara, Nimita H et al. (2012) Rotavirus-induced IFN-? promotes anti-viral signaling and apoptosis that modulate viral replication in intestinal epithelial cells. Innate Immun 18:294-306 |
| Frias, A H; Vijay-Kumar, M; Gentsch, J R et al. (2010) Intestinal epithelia activate anti-viral signaling via intracellular sensing of rotavirus structural components. Mucosal Immunol 3:622-32 |
| Ogura, Yasunori; Sutterwala, Fayyaz S; Flavell, Richard A (2006) The inflammasome: first line of the immune response to cell stress. Cell 126:659-62 |
