MSU Superfund Projects and Cores:

Project 1: Characterization of the Pathways Linking Ah Receptor Activation with Altered B Cell Differentiation Using an Integrated Experimental and Computational Modeling Approach

Project 2: Dissecting the Signaling Network for Ah Receptor-mediated Bcell Toxicity

Project 3: Non-Additive Ah Receptor Ligand Interactions

Project 4: Influence of Ah Receptor Ligands on Inflammatory Responses: Consequences for Tissue Injury and Gene Expression

Project 5: A Proteomic Analysis of the AHR signaling Network

Project 6: Molecular Insight into Polyaromatic Toxicant Degradation by Microbial Communities

Project 7: Geochemical Controls on the Adsorption, Bioavailability, and Long-term Environmental Fate of Dioxins, PCBs, and PAHs

Core A: Administration

Core B: Research Translation

Core C: Computational Modeling of Mammalian Biomolecular Response

Core D: Biomedical Informatics

Core E: Environmental Molecular Analysis

Return to the MSU Superfund Main Page

Link to the NIEHS SBRP site

Superfund Project 2

Dissecting the Signaling Network
for Ah Receptor-mediated Bcell Toxicity

A comprehensive evaluation of human exposure pathways at Superfund sites reveals that contaminants functioning as Ahr agonists present a significant risk to surrounding residents and immunological effects are one of the least studied toxciological end points. The primary objectives of this project are two-fold: (1) dissect the gene expression cascade involved in suppression of B-cell activation and IgM secretion following exposure to Ahr agonists; (2) combine information on the gene expression cascade with a comprehensive survey of protein interactions (Project 5, LaPres) and focused molecular experimentation (this project and Project 1, Kaminski) to create an integrated, systems-level model of the role of Ahr in the B-cell differentiation signaling network. 

The figure at left is a schematic representation of the Ahr signaling pathway.

We hypothesize that multiple nodes in the B-cell differentiation network are regulated by the Ahr. By dissecting the interrelationships within the gene expression cascade together with a comprehensive protein interaction map, we will be able to mechanistically model the dose-response behavior for Ahr B-cell immunotoxicity. This hypothesis will be tested using a unique combination of genomic and computational tools that dissect the transcriptional cascades following exposure to an Ahr agonist and infer the corresponding structure of the cellular signaling network for computational modeling.

The specific aims of this project are:

1. identify Ahr-dependent alterations in the B-cell gene expression cascade following activation with LPS and exposure to the prototype Ahr agonist TCDD;
2. characterize the direct, cis-acting effects of Ahr activation on primary changes in gene expression in the B-cell differentiation cascade;
3. delineate the interrelationships between primary gene expression events and secondary and tertiary gene expression changes for Ahr-mediated alterations in B-cell differentiation; and
4. combine information on the Ahr-regulated B-cell gene expression cascade with a comprehensive survey of protein interactions and focused molecular experimentation to create an integrated, systems-level computational model of the Ahr and B-cell differentiation signaling network. 

Through these specific aims, we will develop a systems-level approach will provide a quantitative and mechanistic understanding of the cellular signaling network involved in the suppression of B-cell differentiation by Ahr agonists. Specifically, genomic tools will provide snapshots into transcriptional responses and functional relationships between genes in the B-cell differentiation pathway, while computational modeling will be used to provide a quantitative biological structure to the signaling network. The development of a systems approach is significant for the environmental health community as a whole by providing a mechanism to systematically investigate the cause-and-effect relationships contained within the lists of altered genes and the underlying logic of the signaling network involved in producing the toxicological effect at environmentally relevant doses.

Russell S. Thomas, Ph.D.
Project Leader
Hamner Institutes for Health Sciences

Melvin E. Andersen, Ph.D.
Co-Investigator
Hamner Institutes for Health Sciences

Norbert E. Kaminski, Ph.D.
Principal Investigator and Co-Investigator
Michigan State University