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Project 1

A Mouse Strain That Exhibits Elevated Sensitivity to Chemical Carcinogens and Hepatotoxins and the Mechanism Underlying That Increase

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Dr. Michael Karin, Project Leader

Project scientists are investigating the role of stress activated protein kinases in mammalian response to oxidative stress, identifying new components of this induction response, and determining the mechanism of gene induction by exposure to a few model toxicants found at Superfund sites, such as arsenite and carbon tetrachloride. The researchers are using a variety of genetic, cell biological and biochemical approaches to search for new regulatory molecules, including protein kinases and transcription factors that are involved in the oxidative stress response. The ability of such genetic alterations to affect how these animals, or cells derived from them, withstand exposure to Superfund site toxicants is being examined. Researchers are creating gene arrays, cell lines and transgenic mice that can be used as biosensors for monitoring exposure to toxicants that cause oxidative stress. Additionally, strains of mice that are deficient in activation of the protective response to oxidative stress are being created. Such mice should be supersensitive to pro-oxidants and thus will facilitate the detection and evaluation of new suspected toxicants and mixtures of chemicals from Superfund Sites for their ability to cause oxidative stress mediated toxicity.

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