The current focus of the project in our laboratory is to understand the biological affects of the molecular disruption in the AbcA13 gene in Tg.AC mice. The transgenic mouse model we are currently employing for this work is Tg.AC. At the programmatic level, the Tg.AC mouse model is being evaluated by the National Toxicology Program (NTP) as an adjunct to the conventional two-year bioassay. The short-term 26-week bioassay relies on the empirical observation that Tg.AC transgenic mice produce skin papillomas when topically treated with chemical carcinogens. Created on the FVB/N mouse, only one of five founder lines displayed the unique characteristics now associated with the Tg.AC mouse. Tg.AC transgenic mice carry a transgene consisting of an oncogenic v-Ha-ras coding region flanked 5 by a mouse zeta-globin promoter and 3 by an SV-40 polyadenylation sequence. Located proximal to the centromere on chromosome 11, the transgene is transcriptionally silent until activated by full thickness wounding, UV light, or chemical carcinogens. This discriminating tumorigenic response does not occur when Tg.AC mice are treated with structurally similar non-carcinogenic chemicals. Expression of the transgene is a required early event that drives cellular proliferation resulting in clonal expansion and tumor formation. Genetic and epigenetic mechanism may contribute to this induced response In our recent molecular studies of the transgene integration site we discovered a new ABC oxysterol transport gene. This gene appears to transport signaling lipids and may be responsible for the transcriptional activation of the ras gene in Tg.AC mice. We are continuing to investigate the role ABCa13 plays in the transcriptional activation of the transgene. To date we have determined that the transgene has compromised the expression of the transporter. This interference of expression results in discrete phenotype changes in Tg.AC mice ras expression (NR).

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES100610-07
Application #
7734520
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2008
Total Cost
$880,687
Indirect Cost
City
State
Country
United States
Zip Code
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