Toxicogenomics and Genetics Group
Richard S. (Rick) Paules, Ph.D.
Senior Scientist/Group Leader
The Toxicogenomics and Genetics Group looks at global transcriptomic responses to environmental stresses that are linked with injury and disease processes, as well as genetic variations that may increase susceptibility to toxicity and disease processes following environmental exposures.
The group is integrating conventional studies of environmental exposures and toxicity with global "omics" approaches, or toxicogenomics. These studies are designed to relate alterations in global gene expression to adverse events as defined by conventional parameters of toxicity and pathology. As part of the Toxicology in the 21st Century Partnership (or "Tox21") (642KB) efforts, the group is working with its federal partners to select and evaluate a gene set of approximately 1000 genes that will be used to query gene expression as a “reduced representation” of the whole-genome transcriptome.
The goal is to implement this gene set (the “G1000”) in a high-throughput, cost effective measurement technology (the “G1000 Platform”). The G1000 will be used to measure whole-genome effects in a comprehensive variety of biological contexts. A primary use will be to screen chemicals for toxicological research applications. Studies will be designed to provide insight into mechanisms of injury and disease as well as to establish signatures of adverse effects to develop putative biomarkers.
The group also develops new approaches that can be used to understand genetic and epigenetic differences in susceptibility to toxicity and disease. Of particular interest are approaches that will utilize embryonic stem or induced pluripotent stem cells derived from mice from the Diversity Outcross (DO) or the Collaborative Cross (CC) populations to attempt to recapitulate the genetic diversity of the human population. These cells can then be utilized in mapping toxicity and disease susceptibility loci, using both traditional QTL and eQTL approaches. It is anticipated that these cells will also be useful in studying not only genetic but also epigenetic alterations that can contribute to toxicity and disease processes.
Using the tools of toxicology, bioinformatics and comparative genetic analysis, the identification of human orthologs of causally related animal genes will aid the extrapolation between animal models and human toxicity and disease related to environmental, occupational, and/or medicinal exposures.
Major areas of research:
- Molecular mechanisms of response to environmental stresses
- Phenotypic anchoring of adverse endpoints via toxicogenomics use of the G1000
- Population-level range of biological response to exposure related toxicity and disease using in vitro and in vivo based models for human populations
- Genetic or epigenetic basis for the mechanism/mode of action of disease causing exposures
- Using genetic and genomics to bridge the responses to environmental exposures between model organisms and humans
- Understanding mechanisms of liver injury in humans from acetaminophen
- Developing blood-derived genomic biomarkers of drug-induced liver injury in humans
- Identifying putative biomarkers and surrogate biomarkers of toxicity
- Developing the Tox21 “1000 Gene” set to be used in the G1000 project
- Implementing the “1000 Gene” set in a high-throughput G1000 platform for using in determining profiles of adverse events and dose-response/kinetic characteristics of exposures to environmental toxicants
Richard S. Paules, Ph.D., heads the Toxicogenomics and Genetics Group and directs the NIEHS Molecular Genomics Core within the Laboratory of Toxicology and Pharmacology. He received his Ph.D. from the Department of Pathology at the University of North Carolina at Chapel Hill in 1984. He has authored over 90 peer-reviewed articles in leading biomedical journals, as well as 18 book chapters and invited publications. He holds appointments as Adjunct Professor in the Department of Pathology and Laboratory Medicine and Adjunct Member of the Lineberger Comprehensive Cancer Center at UNC-CH. He also serves as Associate Editor of Physiological Genomics and BMC Genomics and serves on the editorial review board of Environmental Heath Perspectives. Since joining the NIEHS, Paules has been recognized with four NIH Merit Awards, the NIH Director's Award and the Society of Toxicology’s 2010 Leading Edge in Basic Science Award.
- Systematic Variation Normalization (SVN)
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