Abstract

The long-term goal of this proposal is to identify genes that are directly responsible for lung tumor resistance to chemical carcinogens.
The specific aims are: 1) Fine mapping of QTLs from a 20-30 cM region to a 1-2 cM subregion of the chromosome, which will be accomplished by the following two complementary approaches. The first is to develop a series of congenic mice through repeated backcrossing with the parental strain carrying the resistance allele. The resulting congenic strain of mice will then be used to generate congenic mapping analysis of the chromosomal regions associated with the QTLs. The second is to conduct deletion mapping analysis of the chromosomal regions associated with the QTLs in mouse lung tumors derived from F1 hybrid mice, and to define a minimal region of chromosomal loss for each QTL. 2) Positional cloning of selected QTLs. A contig containing overlapping BAC/P1 clones for each fine mapped QTL (1-2 cM) will be constructed using closely linked polymorphic markers and genes. Candidate genes will be isolated by direct screening of cDNA libraries with the BAC/P1 clones. Candidate genes will be analyzed for sequence variations in the coding region and differences in RNA expression between parental alleles. 3) Functional characterizations will be conducted under this proposal to either confirm or eliminate candidate genes for mouse lung tumor resistance QTLs.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA078797-05
Application #
6513165
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Yang, Shen K
Project Start
1998-09-04
Project End
2004-06-30
Budget Start
2002-07-01
Budget End
2004-06-30
Support Year
5
Fiscal Year
2002
Total Cost
$242,508
Indirect Cost

  Institution

Name
Ohio State University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210

  Publications

Vikis, Haris G; Jackson, Erin N; Krupnick, Alexander S et al. (2010) Strain-specific susceptibility for pulmonary metastasis of sarcoma 180 cells in inbred mice. Cancer Res 70:4859-67
Wang, Y; Zhang, Z; Lubet, R A et al. (2006) A mouse model for tumor progression of lung cancer in ras and p53 transgenic mice. Oncogene 25:1277-80
Zhang, Zhongqiu; Yao, Ruisheng; Li, Jie et al. (2005) Induction of invasive mouse skin carcinomas in transgenic mice with mutations in both H-ras and p53. Mol Cancer Res 3:563-74
Bonner, Allison E; Lemon, William J; Devereux, Theodora R et al. (2004) Molecular profiling of mouse lung tumors: association with tumor progression, lung development, and human lung adenocarcinomas. Oncogene 23:1166-76
Wang, Min; Lemon, William J; Liu, Gongjie et al. (2003) Fine mapping and identification of candidate pulmonary adenoma susceptibility 1 genes using advanced intercross lines. Cancer Res 63:3317-24
Zhang, Zhongqiu; Futamura, Manabu; Vikis, Haris G et al. (2003) Positional cloning of the major quantitative trait locus underlying lung tumor susceptibility in mice. Proc Natl Acad Sci U S A 100:12642-7
Li, Jie; Zhang, Zhongqiu; Dai, Zunyan et al. (2003) RASSF1A promoter methylation and Kras2 mutations in non small cell lung cancer. Neoplasia 5:362-6
Li, Jie; Zhang, Zhongqiu; Dai, Zunyan et al. (2003) LOH of chromosome 12p correlates with Kras2 mutation in non-small cell lung cancer. Oncogene 22:1243-6
Lemon, W J; Swinton, C H; Wang, M et al. (2003) Single nucleotide polymorphism (SNP) analysis of mouse pulmonary adenoma susceptibility loci 1-4 for identification of candidate genes. J Med Genet 40:e36
Zhang, Zhongqiu; Wang, Yian; Lantry, Laura E et al. (2003) Farnesyltransferase inhibitors are potent lung cancer chemopreventive agents in A/J mice with a dominant-negative p53 and/or heterozygous deletion of Ink4a/Arf. Oncogene 22:6257-65

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