Currently, a wealth of transgenic and mutant mouse models are being generated for studying the role of defective DNA repair and cell cycle control in environmentally induced human diseases, such as cancer. One of the fundamental problems in the development and utilization of such models is their short-term focus. Very few, if any, of the current models are designed to study human disease and functional decline during the aging process. This is in spite of the demonstrated relationship between adverse effects related to aging and long-term exposure to environmental and endogenous DNA damaging agents. Thus, there is a need to focus mouse model development and derivation for the specific purpose of studying DNA repair in relation to environmental exposures in the context of the aging process. The team of investigators involved in this application wishes to become a component of the Comparative Mouse Genomics Centers Consortium. They will bring their expertise in DNA repair, cell cycle control, mouse genetic modeling and genetic toxicology, and the generation of molecular databases, with a unique focus on aging and its related intrinsic and environmentally induced disease sequelae. The mouse models proposed to be derived are mimics of human p53, base excision repair, and nucleotide excision repair gene variants. The investigators propose to use their knowledge and technology base in life span studies, exposure studies, molecular end point studies, and molecular effect databases to characterize and validate these variants.
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