The goal of this proposal is to identify the Par2 gene, which is responsible for lung tumor resistance in the BALB/cByJ mouse to chemical carcinogens. Although lung cancer is largely associated with smoking, there is strong evidence for genetic susceptibility and gene-environment interactions in the development of lung cancer. Inbred mouse models offer an effective means of identifying candidate lung cancer modifiers since genetic heterogeneity and enormous variation in exposure levels to environmental agents makes it difficult to identify lung cancer susceptibility loci in humans. A major quantitative trait loci (QTL) locus named pulmonary adenoma resistance gene 2 (Par2) responsible for 50% of variance in tumor multiplicity between the A/J mouse and the BALB/cByJ mouse has been mapped to mouse chromosomes 18. The QTL mapping result has been confirmed by the production of congenic strains in which high lung tumor susceptibility (A/J) allele was substituted onto the genetic background of the BALB/cJ mouse. In this proposal, we will fine map the Par2 QTL by progressively reducing the QTL region through the production of subcongenic mouse strains to narrow it to a size of around 0.2-0.5 cM. 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 BALB/cJ mice. The functional role of the candidate Par2 gene will then be evaluated by constructing knock-in mice with the A/J Par2 allele replacing the BALB/cJ allele. The resulting mouse will be subjected to lung carcinogenesis assay to confirm the Par2 gene. Since the Par2 has been shown to be a negative modifier of the Pas1 QTL, we will produce double congenic strains that contain the Par2 locus in the presence or absence of the Pas1 locus. Comparisons of lung tumor response among double and single congenics will allow definition of interactions between the loci involved. The significance of these studies is that they will identify the Par2 gene whose human homologue may predispose some individuals to lung cancer.
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