? Support is requested to continue human health-oriented research on risks from exposure to chemicals commonly found in Superfund sites and on remediation technologies to eliminate the potential for exposure to chemicals from those sites. The pollutants under investigation are a subclass of chemicals belonging to the halogenated aromatic hydrocarbon family that bind and activate the aryl hydrocarbon receptor (AhR).These chemicals, which include chlorinated dibenzo-p-dioxins, dibenzofurans, biphenyls and polycyclic aromatic hydrocarbons, are environmentally persistent lipid soluble compounds that accumulate in the food chain and lead to human and wildlife exposure. A highly integrated, multidisciplinary research program is proposed consisting of seven research projects and four supporting core units. The research team of 27 investigators includes faculty at Michigan State University (20), CUT Centers for Health Research (4), Rutgers (2), and Purdue University (1). The central overarching theme of the proposed new program is to define specific aspects of environmental, microbial and mammalian biomolecular responses to environmental contaminants that act as ligands for the AhR. The major research thrusts are in three areas: (1) characterizing the diversity of dehalogenases and oxygenase gene sequences in microbial populations indigenous to soils, sediments and groundwater that metabolize AhR ligands; (2) defining the geochemical parameters governing adsorbtion, bioavailability and long-term fate of AhR ligands through interactions with clays; and(3) elucidation and computational modeling of the biochemical pathways and their interactions with the ligand-activated AhR, which cause altered responses in the liver and the immune system, specifically in Bcells. Two major goals of the new program are to characterize molecular mechanisms of AhR ligand interactions with specific abiotic and biotic processes and to develop new tools that can be used to more accurately estimate the fate, microbial biotransformation and human risk associated with AhR ligands contaminating the environment. Two support core facilities will assist the biomedical projects, one in the areas of bioinformatics and a second in developing dynamic computational models of mammalian biological responses induced by AhR ligands. A third core facility will provide support for the non-biomedical projects in three areas related to analysis of microbial-derived enzymes: microarray development and enhancement, automated bioinformatics analysis of PCR product sequences and biodegradative gene clusters, and high throughput screening and sequencing. In addition, a Research Translation core will communicate important research findings and outcomes emanating from the program to appropriate target audiences in government, industry and academia. ? ? ?
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