Analysis of chromosomal regions which regulate susceptibility to inflammation and lung carcinogenesis in selected mouse lines

Abstract

Mice selected for high acute inflammatory response (AIRmax) are resistant while the low responder AIRmin mice are susceptible to lung tumorigenesis, suggesting that genetic selection for inflammatory response also selected for alleles of genes implicated in cancer susceptibility. In order to map these genes, a genome wide linkage assay with polymorphic SNP markers was carried out in intercross F2 (AIRmax x AIRmin) mice. We identified the Irm1 locus (Inflammatory response modulator 1) linked to inflammation parameters, such as IL-1beta production and infiltrated cells and proteins at the inflammatory site in a 3.5Mb interval at chromosome 7. Another region in distal chromosome 6 was linked to lung tumor multiplicity at the Pas1 locus (Pulmonary adenoma susceptibility 1) to which the Kras gene maps. This region was also associated with inflammation phenotypes. Herein we intend to compare the DNA sequences chromosome 7 interval aiming to the identification of polymorphisms in coding or in regulatory regions of candidate genes and to compare the gene transcript levels in IL-1beta producing cells from AIRmax and AIRmin mice. Kras isoforms transcription and Kras activating mutations will be analyzed in lung tumors from F2 mice, in order to identify regulatory genetic elements of Kras expression and mutability. (AU)