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Project 3

Toxicogenomic Analysis of Nuclear Xenobiotic Receptors, PXR and CAR, in Chemical Metabolism and Human Health

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Dr. Ronald Evans, Project Leader

Xenobiotic nuclear receptors, PXR and CAR, are activated by numerous chemicals and induce the Phase I, II and III clearance pathways through their induced association with specific transcriptional coactivators. Efforts in Dr. Evan’s laboratory hypothesize that the adverse effects of some toxic environmental agents are mediated in part through interactions with PXR and/or CAR, which can ultimately lead to both acute and chronic perturbations of the hepatic clearance system, production of super toxic metabolites and endocrine disruption. To test these ideas, Dr. Evan’s will: (1) develop cell-based reporter systems based on cloned human and rodent receptors and screen environmental chemicals in their ability to bind and activate PXR and/or CAR. (2) perform DNA microarray analysis to define the genomic targets of environmental toxins in wild type or PXR and/or CAR deficient cells. (3) study the in vivo effects of chemical exposure (low- and high-dose and short- and long-term treatment) using PXR and CAR knockout mice and transgenic humanized mouse models that we have recently developed. It is anticipated that these experiments will uncover the molecular mechanisms by which environmental chemicals exert adverse effects and will also provide unique tools to predict toxicity.

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