TOXICOLOGY OF ENVIRONMENTAL CHEMICALS

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DESCRIPTION (provided by applicant): Research in this competitive PPG renewal, Toxicity of Environmental Chemicals, is focused on understanding the mechanisms of toxicity of selected environmental chemicals and the basic biochemical mechanisms involving the immune system, cellular function, oxidative stress and gene expression that may be altered through adverse effects of environmental chemicals. The overriding theme of this interdisciplinary research PPG is protein-ligand, protein-protein interactions and cellular signaling pathways. This PPG will depend on a combination of experimental strategies involving whole animal models, and biochemical and molecular biological methods; a variety of biophysical methods including mass spectrometry and kinetics to address questions relating to regulation in the immune system and cell adhesion to the extracellular matrix; nitration of proteins by peroxynitrite; and signaling pathways in RA-dependent transcription factors. These studies will specifically focus on: (1) identifying the signaling pathways in T lymphocytes that are altered by TCDD-induced AhR activation leading to T cell dysfunction, (2) determining the mechanisms involved in the regulation of cell adhesion and motility by PDGF, (3) elucidating the mechanisms by which oxidation of proteins by peroxynitrite interferes with protein-protein interactions, (4) investigating the role of GRASP and the tumor suppressor, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), in signaling pathways induced by RA, and (5) elucidating the mechanisms and dynamics involved in RA receptor-mediated gene expression induced by RA, methoprene acid, and other agonists. Experimental approaches to be used include flow cytometry, UV circular dichroism, fluorescence, quench and stopped-flow kinetics, and new techniques developed under the existing PPG (ES00040), including high speed cell sorting, a differential proteolytic sensitivity assay, H/D exchange, and singular value decomposition for analyzing multistate unfolding events at equilibrium. A Mass Spectrometry Core will provide mass spectrometry support for the individual Projects. The 5 highly interdisciplinary Projects will answer significant unresolved questions concerning the effects of specific environmental chemicals on protein-protein interactions and important cellular signaling pathways.