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.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR020152-08
Application #
8360725
Study Section
Special Emphasis Panel (ZRR1-RI-B (01))
Project Start
2011-08-01
Project End
2012-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
8
Fiscal Year
2011
Total Cost
$279,468
Indirect Cost
Name
Tulane University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Wu, Victor J; Pang, Darren; Tang, Wendell W et al. (2017) Obesity, age, ethnicity, and clinical features of prostate cancer patients. Am J Clin Exp Urol 5:1-9
Zhang, Q; Liu, S; Parajuli, K R et al. (2017) Interleukin-17 promotes prostate cancer via MMP7-induced epithelial-to-mesenchymal transition. Oncogene 36:687-699
Gopalakrishnan, Anusha M; Aly, Ahmed S I; Aravind, L et al. (2017) Multifunctional Involvement of a C2H2 Zinc Finger Protein (PbZfp) in Malaria Transmission, Histone Modification, and Susceptibility to DNA Damage Response. MBio 8:
Liu, Yao-Zhong; Zhang, Lei; Roy-Engel, Astrid M et al. (2017) Carcinogenic effects of oil dispersants: A KEGG pathway-based RNA-seq study of human airway epithelial cells. Gene 602:16-23
Yang, Lingyun; Huang, Feng; Mei, Jiandong et al. (2017) Posttranscriptional Control of PD-L1 Expression by 17?-Estradiol via PI3K/Akt Signaling Pathway in ER?-Positive Cancer Cell Lines. Int J Gynecol Cancer 27:196-205
Wang, Xun; Yang, Lingyun; Huang, Feng et al. (2017) Inflammatory cytokines IL-17 and TNF-? up-regulate PD-L1 expression in human prostate and colon cancer cells. Immunol Lett 184:7-14
Ma, Lin; Li, Jingwu; Nie, Qiang et al. (2017) Organoid culture of human prostate cancer cell lines LNCaP and C4-2B. Am J Clin Exp Urol 5:25-33
Servant, Geraldine; Streva, Vincent A; Derbes, Rebecca S et al. (2017) The Nucleotide Excision Repair Pathway Limits L1 Retrotransposition. Genetics 205:139-153
Martin, Elizabeth C; Conger, Adrienne K; Yan, Thomas J et al. (2017) MicroRNA-335-5p and -3p synergize to inhibit estrogen receptor alpha expression and promote tamoxifen resistance. FEBS Lett 591:382-392
Zhang, Qiuyang; Liu, Sen; Ge, Dongxia et al. (2017) Targeting Th17-IL-17 Pathway in Prevention of Micro-Invasive Prostate Cancer in a Mouse Model. Prostate 77:888-899

Showing the most recent 10 out of 154 publications