Superfund Research Program

Biomedical Informatics Core

Project Leader: Russell S. Thomas (The Hamner Institutes for Health Sciences)
Grant Number: P42ES004911
Funding Period: 2006-2013

Project-Specific Links

Final Progress Reports

Year:   2012 

The proposed research activities investigating the biomolecular responses to aryl-hydrocarbon receptor (AhR) ligands relies heavily on the application of modern genomic and proteomic tools. In using these tools, significant amounts of data will be generated that must be properly managed, stored, analyzed, and mined in order to derive knowledge from the mass of information. The primary objective of the Biomedical Informatics Core (BIC) will be to enable the analysis of genomic and proteomic data in the most efficient manner possible.

The BIC physically resides at both The Hamner Institutes for Health Sciences (Hamner) and Michigan State University (MSU) to allow for greater personnel interaction between project leaders and informatics personnel. At the Hamner, the initial focus this year was on completion of a tool that will allow the normalization and processing of extremely large microarray datasets, the evaluation of published tools that allow the inference of gene regulatory networks from large microarray datasets, and promoting the use of the BMDExpress tool. The normalization tool allows processing extremely large datasets include all arrays of a given type in the Gene Expression Omnibus and the Iconix gene expression dataset acquired by the National Toxicology Program. The normalization tool was successfully completed. The BMDExpress is a Java application used to analyze dose-response data from microarray experiments using benchmark dose methods. Interest has been growing within the regulatory community on using the BMDExpress tool to analyze gene expression data in a risk assessment context. Training was provided to Health Canada on using BMDExpress. Apart from the development of the normalization tool and the BMDExpress training, the BIC was focused on the analysis of the proteomic experiments in the Dissecting the Signaling Network for Ah Receptor-mediated B-cell Toxicity and A Proteomic Analysis of the AHR signaling Network projects to allow characterization of the protein interaction network for the AhR.

The focus of the MSU BIC for this grant period was on the analysis of the in vivo transcriptomic and metabolomic studies. In the Non-Additive Ah Receptor Ligand Interactions project, dose-response studies in mice treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces hepatic steatosis which progresses to hepatosteatosis with evidence of fibrosis following repeated doses (every 4 days) at 28 days of exposure. The bioinformatic analyses were used to relate AhR enrichment to dioxin response element (DRE) dependent and independent gene expression related to lipid transport, processing and metabolism. The integration of over-represented functional analysis, phenotypic and metabolomic data with the progressive development of hepatosteatosis with fibrosis is leading to a novel hypothesis regarding the potential role of AhR in metabolic diseases including metabolic syndrome, diabetes and hepatocellular carcinoma. This data provides a foundation for the development of an AhR-mediated gene expression network associated with AhR-mediated metabolic disease in the mouse with relevance to human hepatic disease.