Lipids play crucial roles in metabolism, immunity and cancer. In addition to their function as inflammatory mediators, lipids serve as antigens presented by CD1d and activate a subset of T cells called natural killer T (NKT) cells. While NKT cells are critical for human immunity, their uncontrolled activation contributes to inflammatory bowel disease (IBD), a group of diseases characterized by chronic intestinal inflammation and an increased risk of colorectal cancer (CRC). Specifically, NKT cells are the major source of pathogenic TH2 cytokines in the inflammatory bowel disease ulcerative colitis (UC), are sufficient to cause intestinal inflammation in mice, and are required for colitis and colitis-associated cancer in a mouse model of UC. These observations suggest that targeting of lipid antigen presentation may be of therapeutic value in IBD, where current therapies are of limited efficacy and aim at control rather than cure of disease.Here, I propose to identify the lipid antigens responsible for NKT cell-mediated intestinal inflammation and colitis-associated cancer in human IBD and mouse models of intestinal inflammation and to develop therapeutic strategies for interference with pathogenic lipid antigen presentation. Specifically, I propose to characterize the intestinal inflammation- and cancer-associated CD1d lipidome based on novel in vitro and in vivo models of cleavable CD1d and a recently established lipidomics approach. Furthermore, I propose to develop strategies for inhibition of the generation, loading and presentation of inflammation- and cancer-associated lipid antigens. These studies combine biochemical, immunological and high-throughput technologies in an interdisciplinary manner to provide the knowledge required for the generation of novel, efficacious therapies for the treatment of IBD. These studies will have major implications for IBD and other inflammatory, infectious, and neoplastic diseases at mucosal barriers.