This application will focus on genetic susceptibility to lung adenoma induction to environmental carcinogens. Linkage analysis previously mapped a lung adenoma resistance quantitative trait locus (QTL) named pulmonary adenoma resistance 1 locus or Par1 which is located on mouse chromosome 11. The Par1 locus confers protection against lung adenoma development. Contributed by M. spretus allele, Par1 locus accounts for 23% of lung adenoma resistance phenotype to chemical carcinogens when co-expressed with highly penetrant Pas1 allele of the A/J strain. The goal of this proposal is to identify the Par1 gene, which is responsible for lung adenoma resistance to chemical carcinogens. The Par1 QTL mapping result has been confirmed by the production of congenic strains in which adenoma resistant M. spretus allele was substituted onto the genetic background of the A/J mouse. Next, the Par1 locus will be fine-mapped by progressively reducing the QTL region through the production of sub-congenic mouse strains to narrow it to a size of around 0.2-0.5 cM, which is expected to be small enough for positional cloning. DNA sequences of the entire narrowed region will be obtained through completed mouse genomic databases. New and known genes in the target region will be identified and candidate genes will be sought based on known or deduced function and/or differences in expression between A/J mice and M. spretus mice. Effect of the candidate Par1 genes on tumorigenic and growth characteristics of mouse lung cells will be examined in vitro. The functional role of the candidate Par1 gene in mouse lung carcinogenesis will be evaluated by constructing knock-in mice. The resulting knock-in mice will be subjected to lung carcinogenesis assay to confirm the Par1 gene. The significance of these studies is that they will identify the Par1 gene and facilitate our understanding of genetic basis of lung adenoma induction by environmental carcinogens. ? ?

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Tinkle, Sally S
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Washington University
Schools of Medicine
Saint Louis
United States
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Liu, Pengyuan; Yang, Ping; Wu, Xifeng et al. (2010) A second genetic variant on chromosome 15q24-25.1 associates with lung cancer. Cancer Res 70:3128-35
Lu, Y; Liu, P; James, M et al. (2010) Genetic variants cis-regulating Xrn2 expression contribute to the risk of spontaneous lung tumor. Oncogene 29:1041-9
You, Ming; Wang, Daolong; Liu, Pengyuan et al. (2009) Fine mapping of chromosome 6q23-25 region in familial lung cancer families reveals RGS17 as a likely candidate gene. Clin Cancer Res 15:2666-74
Liu, Peng-Yuan; Vikis, Haris; James, Michael et al. (2009) Identification of Las2, a major modifier gene affecting the Pas1 mouse lung tumor susceptibility locus. Cancer Res 69:6290-8
Liu, Pengyuan; Vikis, Haris G; Wang, Daolong et al. (2008) Familial aggregation of common sequence variants on 15q24-25.1 in lung cancer. J Natl Cancer Inst 100:1326-30
Wang, Min; Vikis, Haris G; Wang, Yian et al. (2007) Identification of a novel tumor suppressor gene p34 on human chromosome 6q25.1. Cancer Res 67:93-9
Liu, Pengyuan; Vikis, Haris; Lu, Yan et al. (2007) Large-scale in silico mapping of complex quantitative traits in inbred mice. PLoS One 2:e651
Liu, Yan; Vikis, Haris G; Yi, Yijun et al. (2007) Degradation of lung adenoma susceptibility 1, a major candidate mouse lung tumor modifier, is required for cell cycle progression. Cancer Res 67:10207-13
Vikis, Haris; Sato, Mitsuo; James, Michael et al. (2007) EGFR-T790M is a rare lung cancer susceptibility allele with enhanced kinase activity. Cancer Res 67:4665-70
Wang, Min; Zhang, Zhongqiu; Zhang, Zhuo et al. (2007) Fine mapping and candidate gene analyses of pulmonary adenoma resistance 1, a major genetic determinant of mouse lung adenoma resistance. Cancer Res 67:2508-16

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