Genetic linkage studies using various strains of inbred mice have mapped pulmonaryadenoma susceptibility (Pas) and pulmonary adenoma resistance (Par) loci [1,2]. Recently,quantitative trait locus (QTL) mapping also identified specific loci that regulate geneticsusceptibility to pulmonary inflammation using inbred mouse strains [3]. Interestingly, commonchromosomal locations were found to regulate both pulmonary inflammation and carcinogenesissuggesting a causal role of pulmonary inflammation in lung tumor susceptibility [3]. Wehypothesize that genetic modifiers of pulmonary inflammation can be identified using F2 linkagemapping in mice followed by fine mapping strategies.
Four specific aims are proposed toaccomplish our goal.
In Specific Aim 1, we will conduct genetic linkage mapping of pulmonaryinflammation QTL in mice exposed to the lung irritant, butylated hydroxytoluene (BHT). Incombination with the carcinogen 3-methylcholanthrene (MCA), BHT promotes MCA-induced lungtumorigenesis. We propose to use the F2 progeny of two strains of mice (BALB/cByJ andC57BL6/J) with extreme inflammation and inflammation-induced tumor promotion phenotypes.
In Aim 2, we will conduct haplotype and whole-genome linkage disequilibrium analyses to guidediscover new QTLs and guide and inform which loci to target in Aim 3. We have recentlydemonstrated the feasibility of association analysis in the fine mapping and identification ofcandidate susceptibility genes for lung adenocarcinomas [4].
Aim 3 will fine map the major QTLrelated to genetic susceptibility to pulmonary inflammation and tumor promotion by theproduction of congenic strains of mice in which the inflammation susceptible allele is substitutedonto the genetic background of the inflammation resistant mice. The QTL will be fine-mapped byprogressively reducing the QTL region through the production of sub-congenic mouse strains tonarrow it to a size of around 0.5-1 cM.
Aim 4 will identify the candidate gene(s) by positionalcloning. DNA sequences of the fine mapped region will be obtained through comparison ofcompleted mouse genomic databases. Candidate genes will be identified based on identifiedfunctional polymorphisms and differences in expression between the two parental strains of miceat different stages of disease progression. The significance of these studies is that they willidentify candidate pulmonary inflammation susceptibility genes that may also contribute togenetic susceptibility to lung cancer in humans.

Public Health Relevance

Increasing evidence supports a direct link between inflammation and cancer, and lung cancer in particular. Epidemiologic data in humans have shown an increased cancer risk in patients with various inflammatory diseases of the lung, including chronic obstructive pulmonary disease (COPD) and asthma among others. Inflammation was found to enhance the development of lung tumors in mice. Many of the QTLs that control genetic susceptibility to lung inflammation, also co-localize with QTLs that regulate lung tumor susceptibility in mice. Administration of budesonide and indomethacin (with anti-inflammatory activity) inhibit lung tumorigenesis in mice. Finally, inflammation biomarkers including Cox1 and Cox2 are frequently elevated in both mouse and human lung cancers. These associations between inflammation and lung cancer suggest that pulmonary inflammation appears to be a key tumor promotion step during the lung tumorigenesis process. The objective of this proposal is to identify genetic modifiers of pulmonary inflammation. The significance of these studies is that they will identify candidate pulmonary inflammation susceptibility genes that may also contribute to genetic susceptibility to lung cancer in humans.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA134433-04
Application #
8214644
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Blair, Donald G
Project Start
2009-06-10
Project End
2014-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
4
Fiscal Year
2011
Total Cost
$307,951
Indirect Cost
Name
Medical College of Wisconsin
Department
Pharmacology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
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