Research in the competitive Program Project Grant Renewal, """"""""Toxicity of Environmental Chemicals"""""""", is directed toward the understanding of mechanisms of toxicity of selected environmental chemicals, including some halocarbons, that pose human health hazards. The overall theme of the interdisciplinary research will focus on chemically induced toxicity involving proteins, nucleic acids, and gene expression and will be devoted to: (1) mechanisms of chemical interactions including alkylations and receptors alterations, oxidative stress and redox status; (2) effects of such agents on protein structure and function and gene expression including effects of thiol alkylation and/or oxidation on protein structure, dynamics, and folding; (3) mechanisms of effects on the immune and peroxisome systems; and (4) analytical tools, including mass spectrometry and nuclear magnetic resonance (NMR), with which to analyze chemical agents and the nature of their interactions with macromolecules. Research objectives are to: (1) Elucidate the mechanisms and kinetics of protein folding and the effects of oxidation and/or alkylation by environmental chemicals. As a model, the pathway will be mapped for the folding of human recombinant macrophage colony stimulating factor beta including the role of formation and decomposition of kinetic intermediates, the energy barriers on the pathway, and structural changes that occur upon refolding as analyzed by amide deuterium/hydrogen exchange; (2) Understand the toxicity of selected environmental chemicals that, by oxidative stress and/or alkylation of thiols, alter redox strains and alter the structure and functions of the thioredoxin family of proteins-thioredoxin, thioredoxin reductase, and protein disulfide isomerase; (3) Utilize NMR to determine the effects of alkylation and redox status of protein thiols on protein structure, dynamics, and function, and to identify intermediates in protein folding studies; (4) Elucidate the molecular determinants of peroxisome proliferator action that are hypothesized to be mediated via interaction with a specific intracellular receptor protein, peroxisome proliferator-activated receptor PPARalpha. These studies will provide additional basis to better understand the role of environmental chemicals in causing oxidative stress as well as ligand-induced conformational change in the regulatory control of protein structure and function; and (5) Investigate the biochemical and molecular mechanisms underlying alterations in T cell activation induced by the aromatic halocarbon TCDD and elucidate the relationship between altered T cell activation and altered redox status in antigen presenting cells. Of importance is the ability of many chemicals to generate oxidative stress either through intracellular receptors (i.e., Ah receptor, PPARalpha) or through induction of enzymes that enzymes oxidative stress. The five highly interdisciplinary projects will strengthen the effort to answer major questions about the chemical and biological properties of environmental chemicals, and the findings from these projects will be utilized to provide a mechanistic basis for prediction of risks and possible disease associated with human exposure to environmental chemicals.
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