The Ah receptor (AhR) has been shown to be largely responsible for the toxic and tumor promotional properties of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), especially, in rodents. Although the human population is exposed to low levels of TCDD, and related compounds, the actual long term health effect(s) remain to be elucidated. Little is known about the biochemical processes involved in the activation and regulation of this ligand-activated helix-loop helix/basic region transcriptional factor. It is our underlying hypothesis that interspecies differences in toxicity results from differences in the biochemical and transcriptional regulatory pathways for the AhR and Ah receptor nuclear translocator protein (ARNT). In this application the multiple mechanisms of AhR regulation will be examined including the following aims; la) Determine the role of XAP2 in the Ali receptor complex, 1b) Complete the mapping of the phosphorylation sites on XAP2 and determine their possible functional role in regulating AhR activity and levels, 2) Complete mapping of the human AhR and ARNT phosphoamino acid sites and determine their possible role in regulating function, 3a) Determine which domains or subdomains of the Ah receptor transactivation domain are key to the transactivation potential of the AhR and what type of coactivators are recruited to this domain, 3b) Identify and clone unique coactivator proteins that are capable of enhancing or repressing AhR/ARNT gene transcription. We will utilize a variety of techniques, including; AhR/FLAG, XAP2/FLAG, and ARNT/FLAG constructs, transient transfection techniques, radiolabeling of proteins in culture, phosphopeptide mapping, site-directed mutagenesis, and various PCR and library screening/cloning techniques. Collectively, these studies will develop an understanding of the pathway of AhR action and the various points of regulation. This information can then be used to explore developmental-, tissue-, and species-specific differences in toxicity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES004869-16
Application #
6627069
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Heindel, Jerrold
Project Start
1989-01-01
Project End
2005-12-31
Budget Start
2003-01-01
Budget End
2003-12-31
Support Year
16
Fiscal Year
2003
Total Cost
$384,218
Indirect Cost
Name
Pennsylvania State University
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802
Smith, Kayla J; Murray, Iain A; Boyer, Jacob A et al. (2018) Allelic variants of the aryl hydrocarbon receptor differentially influence UVB-mediated skin inflammatory responses in SKH1 mice. Toxicology 394:27-34
Moyer, Benjamin J; Rojas, Itzel Y; Murray, Iain A et al. (2017) Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors activate the aryl hydrocarbon receptor. Toxicol Appl Pharmacol 323:74-80
Hubbard, Troy D; Murray, Iain A; Nichols, Robert G et al. (2017) Dietary Broccoli Impacts Microbial Community Structure and Attenuates Chemically Induced Colitis in Mice in an Ah receptor dependent manner. J Funct Foods 37:685-698
Murray, Iain A; Perdew, Gary H (2017) Ligand activation of the Ah receptor contributes to gastrointestinal homeostasis. Curr Opin Toxicol 2:15-23
Muku, Gulsum E; Lahoti, Tejas S; Murray, Iain A et al. (2017) Ligand-mediated cytoplasmic retention of the Ah receptor inhibits macrophage-mediated acute inflammatory responses. Lab Invest 97:1471-1487
Murray, Iain A; Nichols, Robert G; Zhang, Limin et al. (2016) Expression of the aryl hydrocarbon receptor contributes to the establishment of intestinal microbial community structure in mice. Sci Rep 6:33969
Girer, Nathaniel G; Murray, Iain A; Omiecinski, Curtis J et al. (2016) Hepatic Aryl Hydrocarbon Receptor Attenuates Fibroblast Growth Factor 21 Expression. J Biol Chem 291:15378-87
Gutierrez, Mark A; Davis, Sonnet S; Rosko, Andrew et al. (2016) A novel AhR ligand, 2AI, protects the retina from environmental stress. Sci Rep 6:29025
Hubbard, Troy D; Murray, Iain A; Bisson, William H et al. (2016) Divergent Ah Receptor Ligand Selectivity during Hominin Evolution. Mol Biol Evol 33:2648-58
Zhang, Limin; Nichols, Robert G; Correll, Jared et al. (2015) Persistent Organic Pollutants Modify Gut Microbiota-Host Metabolic Homeostasis in Mice Through Aryl Hydrocarbon Receptor Activation. Environ Health Perspect 123:679-88

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