With the imminent completion of the human genome sequence, scientists are now faced with the daunting task of discovering the biological function of each gene and the consequence of the small variations, or polymorphisms, that make one individual different from another. As these sequence variations are identified, they will undoubtedly be linked to human diseases, including diseases caused by exposure to environmental agents. Transgenic mouse models are very powerful tools for studying the function of genes and gene variants in the context of a whole organism. The proposed mouse models in this application will focus on genes and gene variants involved in cell cycle regulation and DNA damage checkpoint control. Standard transgenic and knockout technologies, as well as new conditional and inducible technologies, will be used to develop these models. These mouse models will be characterized at the histopathological and molecular levels and their response to carcinogenic agents, both chemical and UV radiation, will be analyzed. New functional genomic technologies will be used to perform an in-depth analysis of the changes in gene expression that occur in these mouse models as a result of the specific genetic alterations and in response to carcinogen exposure. The studies will initially be focused on the skin as a model organ system. However, because of the nature of the transgenes and targeting constructs to be used in generating these models, there is also the potential to study other epithelial tissues, including the prostate, mammary gland, thymus, bladder, gall bladder, and upper aerodigestive tract. This group of investigators has expertise in transgenic mouse development, molecular biology (particularly as it relates to the cell cycle), pathology, mouse genetics, carcinogenesis, biostatistics, and functional genomics. The senior investigators have experience in the mouse skin system and have previously worked together to develop and characterize transgenic mouse models. The scientific goals of the proposed studies are to determine the following: 1) the biological properties of a variant of cyclin Dl, 2) the mechanism by which E2Fl suppresses tumorigenesis, 3) the normal function of BRCA1 and PTEN in regulating epithelial tissue homeostasis, and 4) the role of a human p2l polymorphic variant in cancer susceptibility. In addition, the transgenic model approaches and functional genomic tools that will be developed will hopefully be applicable for the development and characterization of additional mouse models based on new discoveries of genetic variations in humans.
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