The Research Support Core A (Computational Core) will develop mathematical models of toxicity pathways perturbed by the environmental contaminant 2,3,7,8-tetrachlorodiobenzo-p-dioxin (TCDD) and related compounds acting via the aryl hydrocarbon receptor (AhR) in support of Research Projects 1, 2, 3, and 4. The proposed models will be structured at a level of detail appropriate to the toxicological endpoints being pursued in the Projects, including immunotoxicity, embryotoxicity and bioenergetic disruption. Representing working hypotheses about the functions of the biological systems being studied and their perturbation by AhR ligands, these models will contain components and interactions that are experimentally well-validated as well as more tentative ones that are the focus of the proposed collaborative research. The potential of multidisciplinary collaborations is exemplified by our success in the last funding period, where coordinated modeling and experimental research has led to much improved understanding of how TCDD suppresses B lymphocyte differentiation through interfering with a bistable gene network and how stochastic gene expression influences the shape of dose response curves. None of these findings could have been made by laboratory experimentation or computational modeling alone. An essential feature of the current proposal is to continue this approach of coordinating laboratory studies with development of computational models, only more extensively.
Specific Aim 1 will implement a model of key regulatory motifs for the activation of primary human B cells by multiple cytokines and antigens, and the disruption of the activation processes by TCDD (in supporting Projects 1 and 2).
Under Specific Aim 2 a multi-organ model of bioenergetics will be developed, with the goal of better understanding how TCDD perturbs hepatic energy homeostasis, leading to fatty liver, alteration of choline metabolism, and disruption of mitochondrial function (in supporting Projects 3 and 4).
Under Specific Aim 3 we will support Project 2 by developing a computational model of early mouse pregnancy to investigate the mechanism by which TCDD suppresses embryonic implantation and study dose responses. Finally, in coordination with the Training Core, Specific Aim 4 will offer computational toxicology courses to Research Project trainees and investigators and the general Superfund Research community.
Core A develops computational models of mechanisms of dioxin toxicity in cooperation with laboratory studies. This integrated approach - computational modeling and laboratory studies - efficiently generates new understanding of toxic mechanisms. The result is better characterization of the exposure-health risk relationship for the immune, liver and developmental effects of dioxins.
|Hwang, Hye Jin; Dornbos, Peter; Steidemann, Michelle et al. (2016) Mitochondrial-targeted aryl hydrocarbon receptor and the impact of 2,3,7,8-tetrachlorodibenzo-p-dioxin on cellular respiration and the mitochondrial proteome. Toxicol Appl Pharmacol 304:121-32|
|Hwang, Hye Jin; Dornbos, Peter; LaPres, John J (2016) Data on AHR-dependent changes in the mitochondrial proteome in response to ,3,7,8-tetrachlorodibenzo-p-dioxin. Data Brief 8:191-5|
|Stedtfeld, Robert D; Williams, Maggie R; Fakher, Umama et al. (2016) Antimicrobial resistance dashboard application for mapping environmental occurrence and resistant pathogens. FEMS Microbiol Ecol 92:|
|Kovalova, Natalia; Manzan, Maria; Crawford, Robert et al. (2016) Role of aryl hydrocarbon receptor polymorphisms on TCDD-mediated CYP1B1 induction and IgM suppression by human B cells. Toxicol Appl Pharmacol 309:15-23|
|Tian, Haoting; Gao, Juan; Li, Hui et al. (2016) Complete Defluorination of Perfluorinated Compounds by Hydrated Electrons Generated from 3-Indole-acetic-acid in Organomodified Montmorillonite. Sci Rep 6:32949|
|Phadnis-Moghe, Ashwini S; Li, Jinpeng; Crawford, Robert B et al. (2016) SHP-1 is directly activated by the aryl hydrocarbon receptor and regulates BCL-6 in the presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Toxicol Appl Pharmacol 310:41-50|
|Nault, Rance; Fader, Kelly A; Kirby, Mathew P et al. (2016) Pyruvate Kinase Isoform Switching and Hepatic Metabolic Reprogramming by the Environmental Contaminant 2,3,7,8-Tetrachlorodibenzo-p-Dioxin. Toxicol Sci 149:358-71|
|Wang, Qiong; Fish, Jordan A; Gilman, Mariah et al. (2015) Xander: employing a novel method for efficient gene-targeted metagenomic assembly. Microbiome 3:32|
|Nault, Rance; Colbry, Dirk; Brandenberger, Christina et al. (2015) Development of a computational high-throughput tool for the quantitative examination of dose-dependent histological features. Toxicol Pathol 43:366-75|
|Liu, Cun; Gu, Cheng; Yu, Kai et al. (2015) Integrating structural and thermodynamic mechanisms for sorption of PCBs by montmorillonite. Environ Sci Technol 49:2796-805|
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