2013 Progress Report: A Multi-scale Dose-response Model of AHR Toxicity Pathway Activation in the Human Liver

EPA Grant Number: R835000
Title: A Multi-scale Dose-response Model of AHR Toxicity Pathway Activation in the Human Liver
Investigators: Bhattacharya, Sudin , Andersen, Melvin E. , Clewell, Harvey , McMullen, Patrick
Current Investigators: Bhattacharya, Sudin
Institution: The Hamner Institutes
EPA Project Officer: Chung, Serena
Project Period: June 1, 2011 through May 30, 2015 (Extended to April 30, 2016)
Project Period Covered by this Report: June 1, 2013 through May 31,2014
Project Amount: $750,000
RFA: Computational Toxicology: Biologically-Based Multi-Scale Modeling (2010) RFA Text |  Recipients Lists
Research Category: Computational Toxicology , Health , Safer Chemicals

Progress Summary:

This year, we used supplementary Hamner funds to carry out a ChIP-seq study of genome-wide PPARα binding in primary human hepatocytes to supplement our gene expression studies in the same cell type. These two data sets were combined into a regulatory network as per the workflow devised in the previous year. This work, combined with downstream functional analysis of perturbed physiological processes, was written up into a manuscript, and submitted for publication in Chemico-Biological Interactions (subsequently accepted and published in 2014). It was also presented as a poster at the 2013 SOT Annual Meeting.

We applied the same workflow to TCDD-induced gene expression data from mouse hepatic tissue and a ChIP-chip study of genome-wide Ah receptor (AhR) binding in mouse liver, published by Tim Zacharewski’s laboratory at Michigan State University, to assemble an in vivo AhR regulatory network for the mouse liver (Figure 1).

The first step towards implementing a liver model in CompuCell3D was taken by creating a two-dimensional section of a virtual liver lobule with a modified cluster aggregation algorithm in Python, which was then incorporated into CompuCell3D (Figure 2). In subsequent steps, a simplified model of the AhR regulatory network will be incorporated into hepatocytes in the CompuCell3D model. 

 

Figure 1. Analysis of TCDD-induced gene expression data and derivation of AhR transcription regulatory network from data sets published by Tim Zacharewski’s laboratory.  

 

Figure 2. Virtual tissue model of liver lobule implemented with a modified cluster aggregation algorithm. 


Journal Articles on this Report : 1 Displayed | Download in RIS Format

Other project views: All 11 publications 3 publications in selected types All 2 journal articles
Type Citation Project Document Sources
Journal Article McMullen PD, Bhattacharya S, Woods CG, Sun B, Yarborough K, Ross SM, Miller ME, McBride MT, LeCluyse EL, Clewell RA, Andersen ME. A map of the PPARĪ± transcription regulatory network for primary human hepatocytes. Chemico-Biological Interactions 2014;209:14-24. R835000 (2013)
R835000 (Final)
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  • Supplemental Keywords:

    Computational model, hepatotoxic injury, dose-response, PPARα, 2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD, aryl hydrocarbon receptor, AhR

    Progress and Final Reports:

    Original Abstract
  • 2011 Progress Report
  • 2012 Progress Report
  • 2014 Progress Report
  • Final Report