My laboratory is interested in defining the pathogenesis of the inflammatory bowel diseases (IBD, comprised of Crohn's disease and ulcerative colitis). We have identified two major genes, namely the Nod2 (CARD15) gene, which confers increased risk solely for Crohn's disease, and the interleukin 23 receptor (IL23R), which confers altered susceptibility for both Crohn's disease and ulcerative colitis. In Nod2, three uncommon amino acid polymorphisms each independently increase risk for CD, and are associated with a decreased capacity to sense bacterial peptidoglycan to activate NF-kB and MAP kinases. At least two independent polymorphisms within the IL23R gene are associated with IBD. Notably, an uncommon amino acid polymorphism, Arg381Gln, confers significant protection against developing IBD. Expression of the IL23R gene is highly regulated, and is induced in TH17 cells. Future studies will be directed toward defining the altered mechanisms associated with IBD-associated Il23R polymorphisms.