The overall objective of this proposal is to develop mouse models for studying the biological function of environmentally sensitive DNA repair/cell cycle control gene variants found in the human population. The capacity for DNA repair is a major influence in the sensitivity to carcinogenic stimuli, so genetic variants must be considered in risk assessment. The concept that common variants in the population contribute to genetic risk for common diseases has triggered intense interest in identifying DNA sequence variants known as single nucleotide polymorphisms (SNPs). However, the functional significance of SNP variants in relation to environmental carcinogens is largely unknown. This proposal is designed to establish a genetically engineered mouse system as a mammalian model for human functional genomics and SNP variant-environment interactions.
The specific aims are 1) Integrate University of Washington Health Sciences resources, including genomics, transgenic technology, mouse genetics, bioinformatics, biostatistics, ecogenetics and environmental health, flow cytometry, whole mouse positron emission tomography (PET) imaging, comparative pathology, and the molecular genetics of DNA repair/cell cycle control genes, into an infrastructure for generating and characterizing SNP mutant mice. 2) Generate SNP mutant mice by gene targeting technology, and characterize and validate these mice using the integrated infrastructure resources established in Aim l. 3) Develop new mouse genomics technology including the prediction of SNP function by three- dimensional, macromolecular protein structure, and whole mouse PET imaging to detect early, environmentally induced tumorigenesis. 4) Establish an electronic database system to enhance communication of unique mouse model data and expertise to the environmental health sciences community. The development of these mouse models will mirror specific human, environmentally responsive polymorphic gene variants found in the general population, and provide a biological system for understanding the functional significance of these polymorphic variants.
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