The goal of this Program-Project Grant (PPG) is to use the tools of modern genetics to elucidate the basic mechanisms that underlie the early stages of hepatocellular carcinogenesis. The focus of the research will be to understand those steps that influence the growth of initiated Cells and to define those events that lead to expression of the malignant phenotype. In classical terms, we are attempting to understand the steps of promotion and progression. Each of these projects will employ complementary approaches to understand these processes, with an emphasis on the use of murine models, chemical modifiers of carcinogenesis, and the tools of molecular genetics. The projects include: (1) Genetic modifiers of murine hepatocarcinogenesis by N. Drinkwater;and (2) Quantifying gene effects on hepatic cancer in vivo by E. Sandgren. Three modest core services (Administration, Animal Technology and Histotechnology) will support this effort. The program maintains a clear focus on hepatocellular cancers, yet, the experiments are designed so that the resultant understanding of liver cancer can be directly applicable to all types of solid tumors. Because of the unique focus and expertise of each of the co-investigators, and due to the exceptional collaborative environment generated by this PPG, the overall contributions that result from the whole program will greatly exceed the sum of the contributions that could be obtained if each project was performed in isolation. Upon completion of this proposal, it is anticipated that we will have furthered our understanding of how chemicals influence the growth controls of initiated cells within the liver. Furthermore, we will have gained molecular insights into the murine model of liver cancer that will allow us to more effectively extrapolate cancer data from animal models to the human condition.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA022484-29
Application #
7603026
Study Section
Subcommittee G - Education (NCI)
Program Officer
Blair, Donald G
Project Start
1997-02-01
Project End
2012-03-31
Budget Start
2009-04-01
Budget End
2012-03-31
Support Year
29
Fiscal Year
2009
Total Cost
$729,047
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
Xia, Chuanwu; Rwere, Freeborn; Im, Sangchoul et al. (2018) Structural and Kinetic Studies of Asp632 Mutants and Fully Reduced NADPH-Cytochrome P450 Oxidoreductase Define the Role of Asp632 Loop Dynamics in the Control of NADPH Binding and Hydride Transfer. Biochemistry 57:945-962
Oberley, Christopher C; Bilger, Andrea; Drinkwater, Norman R (2015) Genetic background determines if Stat5b suppresses or enhances murine hepatocarcinogenesis. Mol Carcinog 54:959-70
Kennedy, Gregory D; Nukaya, Manabu; Moran, Susan M et al. (2014) Liver tumor promotion by 2,3,7,8-tetrachlorodibenzo-p-dioxin is dependent on the aryl hydrocarbon receptor and TNF/IL-1 receptors. Toxicol Sci 140:135-43
Copp, Richard R; Peebles, Daniel D; Soref, Cheryl M et al. (2013) Radioprotective efficacy and toxicity of a new family of aminothiol analogs. Int J Radiat Biol 89:485-92
Figueiredo, Marxa L; Stein, Timothy J; Jochem, Adam et al. (2012) Mutant Hras(G12V) and Kras(G12D) have overlapping, but non-identical effects on hepatocyte growth and transformation frequency in transgenic mice. Liver Int 32:582-91
Stein, Timothy J; Jochem, Adam; Holmes, Katie E et al. (2011) Effect of mutant ?-catenin on liver growth homeostasis and hepatocarcinogenesis in transgenic mice. Liver Int 31:303-12
Copp, Richard R; Peebles, Daniel D; Fahl, William E (2011) Synthesis and growth regulatory activity of a prototype member of a new family of aminothiol radioprotectors. Bioorg Med Chem Lett 21:7426-30
Stein, Timothy J; Bowden, Margaret; Sandgren, Eric P (2011) Minimal cooperation between mutant Hras and c-myc or TGF? in the regulation of mouse hepatocyte growth or transformation in vivo. Liver Int 31:1298-305
Xia, Chuanwu; Hamdane, Djemel; Shen, Anna L et al. (2011) Conformational changes of NADPH-cytochrome P450 oxidoreductase are essential for catalysis and cofactor binding. J Biol Chem 286:16246-60
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

Showing the most recent 10 out of 258 publications