This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Although the precise etiologies of the inflammatory bowel diseases (IBD) are unknown, the involvement of tumor necrosis factor (TNF) in this pathology and its sequellae, including increased vulnerability to colitis-associated carcinoma (CAC), is certain. The goal of this proposal is to understand the role of tumor-necrosis-factor-receptor-1 (TNFR1) in the progresson to colitis-associated carcinoma. TNF exerts its action via 2 cell-surface receptors, TNFR1 and TNFR2. They are involved in the regulation of inflammation, apoptosis and the immune response. Most investigators have found TNFR1 to be protective in the setting of acute injury. We have found previously that mice lacking TNFR1 develop invasive carcinoma following repeated episodes of inflammation. These studies not only confirm the importance of TNF in the linked processes of inflammation and carcinogenesis but highlight the critical function of TNFR1 in the response to injury and protection from invasive disease. Moreover, recent studies by other investigators have suggested that one of the pathways by which TNF promotes carcinogenesis is by stimulating the Wnt/?-catenin pathway in the epithelium. Accordingly, the overall hypothesis to be tested in this proposal is that TNFR1 protects from the development of CAC by inhibiting aberrant Wnt/B-catenin signaling in the colonic epithelial cells. The overall aim, therefore, is to elucidate how TNFR1 protects from colitis-associated carcinoma (CAC). To this end we will use a well-characterized model of murine tumorigensis to dissect the mechanism by which TNFR1 is protective of neoplastic transformation.
In Specific Aim 1 we will establish a timeline and, with a combination of timed sacrifice and surveillance colonoscopy followed by RNA microarray and real-time PCR, correlate specific outcomes with changes in global gene expression.
In Specific Aim 2 we propose to ascertain the link between aberrant Wnt/?-catenin and loss of TNFR1 signaling using cell culture, si RNA, TOP-flash luciferase plasmids and conventional BAT-gal/TNFR1 knockout mice.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Exploratory Grants (P20)
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Special Emphasis Panel (ZRR1-RI-B (01))
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Tulane University
Public Health & Prev Medicine
Schools of Public Health
New Orleans
United States
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