The objective of this proposal is to understand the mechanisms by which environmental chemicals influence liver tumor promotion. To accomplish this task, we propose to use the prototype carcinogen, 2,3,7,8-tetrachlorodibenzo- ? p-dioxin (dioxin), as a promoter of hepatocellular carcinoma in the two-stage mouse model. The choice of dioxin is related to its biological potency and the large volume of genetic and pharmacological evidence that suggests its effects are mediated through a single ligand-activated transcription factor known as the Ah receptor (AHR). Given the central nature of this signaling protein, efforts will be made to elucidate the molecular details of the dioxin-AHR pathway as it relates to liver tumor promotion. To this end, we will first optimize the murine model of liver tumor promotion, with particular emphasis on genetics and statistical power. We will then use gene-targeting approaches to manipulate various functional domains and expression patterns of the AHR, as well as its heterodimeric partner ARNT. In particular, focus will be on determining if dioxin's tumor promoting activity is a cell autonomous process and if it is the direct result of the AHR's or ARNT's activity as transcription factors. This understanding will guide the later experiments that will be directed at identifying those particular transcriptional outputs that lie in the pathway to tumor promotion. In this last respect, emphasis will be placed on direct test for the involvement of candidate genes such as Cyp1a1, Cyp1a2 and Cyp1b1, as well as the IL1-like inflammatory cytokines. As a backup approach, we will begin to develop novel screening approaches to identify candidate genes using high throughput transcriptional profiling of preneoplastic lesions and SiRNA technologies to elucidate functional roles in promotion. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES013566-03
Application #
7276754
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Shreffler, Carol K
Project Start
2005-09-19
Project End
2009-08-31
Budget Start
2007-09-01
Budget End
2009-08-31
Support Year
3
Fiscal Year
2007
Total Cost
$399,025
Indirect Cost
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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Shen, Anna L; O'Leary, Kathleen A; Dubielzig, Richard R et al. (2010) The PPCD1 mouse: characterization of a mouse model for posterior polymorphous corneal dystrophy and identification of a candidate gene. PLoS One 5:e12213
Nukaya, Manabu; Bradfield, Christopher A (2009) Conserved genomic structure of the Cyp1a1 and Cyp1a2 loci and their dioxin responsive elements cluster. Biochem Pharmacol 77:654-9
Nukaya, Manabu; Moran, Susan; Bradfield, Christopher A (2009) The role of the dioxin-responsive element cluster between the Cyp1a1 and Cyp1a2 loci in aryl hydrocarbon receptor biology. Proc Natl Acad Sci U S A 106:4923-8
Bunger, Maureen K; Glover, Edward; Moran, Susan M et al. (2008) Abnormal liver development and resistance to 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity in mice carrying a mutation in the DNA-binding domain of the aryl hydrocarbon receptor. Toxicol Sci 106:83-92