The toxicogenomics research program at the University of North Carolina-Chapel Hill (UNC-CH) is focused on genetic determinants of susceptibility to environmental toxicants and chemotherapeutic drugs. Human and murine model systems will be used to determine the patterns of alterations in gene expression when cells and animals are exposed to several classes of toxins. Toxin classes under study include agents that induce oxidative stress, DNA double strand breaks, alkylation of DNA bases, as well as nuclear receptor agonists. cDNA microarrays containing greater than 10,000 expressed genes will be used to determine for human cells and mice, the dose and time kinetics of toxicant-induced changes in gene expression. In two interactive research projects diploid human mammary epithelial cells, fibroblasts and lymphoblasts, will be treated with doses of toxicants ranging about the mean lethal dose (D/o for inactivation of colony formation). Cell lines with heterozygous and homozygous mutations in the tumor suppressor genes p53, ATM and BRCA1, or with genetic inactivation of suppressor function, will be compared to wildtype lines to establish profiles of genetic susceptibility to toxicant stress. Similarly, a third research project will determine patterns of response to the toxicants in liver, mammary gland and colon of ten strains of mice with varying susceptibilities to carcinogenesis. These studies will determine whether murine strain-dependent susceptibility to carcinogenesis resembles human genetic susceptibility due to mutations in tumor suppressors. A Toxicology Resource Core proposes a demonstration project to determine the profiles of altered gene expression in livers of mice exposed to non-genotoxic chemicals which activate the nuclear receptors, AhR, CAR and PPAR-alpha. The three research projects and the Toxicology Resource Core will be served by an Administrative Core, a Microarray Facility Core, and an lnformatics Facility Core. The UNC-CH toxicogenomics research program has the scientific expertise and organizational infrastructure to provide significant and substantial benefits to the Toxicogenomics Research Consortium.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19ES011391-01
Application #
6440294
Study Section
Special Emphasis Panel (ZES1-LKB-E (RT))
Program Officer
Mcclure, Michael
Project Start
2001-09-25
Project End
2006-08-31
Budget Start
2001-09-25
Budget End
2002-08-31
Support Year
1
Fiscal Year
2001
Total Cost
$1,095,863
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pathology
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Ross, Pamela K; Woods, Courtney G; Bradford, Blair U et al. (2009) Time-course comparison of xenobiotic activators of CAR and PPARalpha in mouse liver. Toxicol Appl Pharmacol 235:199-207
Chen, Bo; Simpson, Dennis A; Zhou, Yingchun et al. (2009) Human papilloma virus type16 E6 deregulates CHK1 and sensitizes human fibroblasts to environmental carcinogens independently of its effect on p53. Cell Cycle 8:1775-87
Harrill, Alison H; Ross, Pamela K; Gatti, Daniel M et al. (2009) Population-based discovery of toxicogenomics biomarkers for hepatotoxicity using a laboratory strain diversity panel. Toxicol Sci 110:235-43
Zhou, Tong; Chou, Jeff; Watkins, Paul B et al. (2009) Toxicogenomics: transcription profiling for toxicology assessment. EXS 99:325-66
Tran, Nancy; Qu, Ping-Ping; Simpson, Dennis A et al. (2009) In silico construction of a protein interaction landscape for nucleotide excision repair. Cell Biochem Biophys 53:101-14
Harrill, Alison H; Watkins, Paul B; Su, Stephen et al. (2009) Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans. Genome Res 19:1507-15
Kaufmann, William K; Nevis, Kathleen R; Qu, Pingping et al. (2008) Defective cell cycle checkpoint functions in melanoma are associated with altered patterns of gene expression. J Invest Dermatol 128:175-87
Pogribny, Igor P; Tryndyak, Volodymyr P; Boureiko, Anna et al. (2008) Mechanisms of peroxisome proliferator-induced DNA hypomethylation in rat liver. Mutat Res 644:17-23
Harrill, Alison Hege; Rusyn, Ivan (2008) Systems biology and functional genomics approaches for the identification of cellular responses to drug toxicity. Expert Opin Drug Metab Toxicol 4:1379-89

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