Superfund Research Program
Research Support A: Computational Modeling of Mammalian Biomolecular Responses
Project Leader: Rory B. Conolly (U.S. Environmental Protection Agency (EPA))
Co-Investigator: Qiang Zhang (Emory University School of Public Health)
Grant Number: P42ES004911
Funding Period: 2006-2021
Project Summary (2013-2021)
The Computational Core develops 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).
The models are 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 TCDD and other AhR agonists, these models contain components and interactions that are experimentally well-validated as well as more tentative ones that are the focus of the collaborative research.
The potential of multidisciplinary collaborations is exemplified by 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 in isolation. An essential feature of this funding period is the continuation of this approach of coordinating laboratory studies with development of computational models, only more extensively.
The Core is implementing a new model of key regulatory motifs in the activation of primary human B cells by multiple cytokines and antigens, and the disruption of this activation process by TCDD. The Core is developing a multiorgan model of bioenergetics, 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. The Core is also 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 Research Translation Core, the Core will offer computational toxicology courses to Research Project staff and the general Superfund Research community.