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. ? ?
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