Patients with inflammatory bowel disease have a substantially increased risk of developing colon cancer. The events that lead from chronic colitis to colon carcinogenesis are not fully understood, but are likely related to an abnormal immune response to the gut microflora and subsequent production of reactive oxygen species, pro-inflammatory cytokines, anti-apoptotic factors, and angiogenic promoting signals during the inflammatory response, that are all conducive to tumorigenesis. The goal of this proposal is to investigate the role of the immune receptor Nod1 in inflammation-associated colon tumorigenesis using a mouse model that involves a single injection of a carcinogen followed by multiple rounds of water containing dextran sulfate sodium (DSS), which causes colitis. Nod1 is a component of the innate immune system that recognizes peptidoglycan moieties found in bacteria, including those of the gut microbiota. Preliminary data suggest that Nod1 signaling by the gut microbiota protects against the development of colon tumors in the setting of chronic inflammation. The mechanism behind this protective effect is unknown, but our data suggest that an interaction between the Nod1 receptor and the gut microbiota is important for maintenance of intestinal homeostasis and tumor suppression. Nod1 knockout mice, compared to wildtype, also have increased basal levels of the adipocytokine, adiponectin, an inflammatory mediator derived primarily from adipose tissue that has also been shown to be important in the development of chemically-induced colitis. Thus, the specific aims of this proposal are: 1) to elucidate the mechanism by which Nod1 signaling protects against colon tumor initiation and progression, 2) to examine the role of the adipocytokine, adiponectin, in the susceptibility of Nod1 knockout mice to tumor formation during chronic inflammation, and 3) to determine the importance of the intestinal microflora in Nod1-mediated tumor suppression. The proposed experiments will provide a deeper understanding of how interactions between the gut microbiota and the innate immune system strongly influence the development of colonic inflammation and subsequent tumorigenesis. In addition, the proposed research will help lay a foundation in the development of a clinical strategy that involves the manipulation of Nod1 signaling to prevent inflammation-associated colon cancer in humans. ? ? ?
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