Dissecting the Signaling Network for Ah Receptor

Michigan State University, East Lansing MI

Investigators

Linked publications & trials

Abstract

A comprehensive evaluation of human exposure pathways at Superfund sites reveals that contaminants[unreadable] functioning as Ahr agonists present a significant risk to surrounding residents and immunological effects are[unreadable] one of the least studied toxciological end points. The primary objectives of this project are two-fold: (1)[unreadable] dissect the gene expression cascade involved in suppression of B-cell activation and IgM secretion following[unreadable] exposure to Ahr agonists; (2) combine information on the gene expression cascade with a comprehensive[unreadable] survey of protein interactions and focused molecular experimentation to create an integrated, systems-level model of the role of Ahr in the B-cell[unreadable] differentiation signaling network. We hypothesize that multiple nodes in the B-cell differentiation network[unreadable] are regulated by the Ahr. By dissecting the interrelationships within the gene expression cascade together[unreadable] with a comprehensive protein interaction map, we will be able to mechanistically model the dose-response[unreadable] behavior for Ahr B-cell immunotoxicity. This hypothesis will be tested using a unique combination of[unreadable] genomic and computational tools that dissect the transcriptional cascades following exposure to an Ahr[unreadable] agonist and infer the corresponding structure of the cellular signaling network for computational modeling.[unreadable] The specific aims of this proposal are: (1) identify Ahr-dependent alterations in the B-cell gene expression[unreadable] cascade following activation with LPS and exposure to the prototype Ahr agonist TCDD; (2) characterize the[unreadable] direct, cis-acting effects of Ahr activation on primary changes in gene expression in the B-cell differentiation[unreadable] cascade; (3) delineate the interrelationships between primary gene expression events and secondary and[unreadable] tertiary gene expression changes for Ahr-mediated alterations in B-cell differentiation; and (4) combine[unreadable] information on the Ahr-regulated B-cell gene expression cascade with a comprehensive survey of protein[unreadable] interactions and focused molecular experimentation to create an integrated, systems-level computational[unreadable] model of the Ahr and B-cell differentiation signaling network. Through these specific aims, we will develop a[unreadable] systems-level approach will provide a quantitative and mechanistic understanding of the cellular signaling[unreadable] network involved in the suppression of B-cell differentiation by Ahr agonists. Specifically, genomic tools will[unreadable] provide snapshots into transcriptional responses and functional relationships between genes in the B-cell[unreadable] differentiation pathway, while computational modeling will be used to provide a quantitative biological[unreadable] structure to the signaling network. The development of a systems approach is significant for the[unreadable] environmental health community as a whole by providing a mechanism to systematically investigate the[unreadable] cause-and-effect relationships contained within the lists of altered genes and the underlying logic of the[unreadable] signaling network involved in producing the toxicological effect at environmentally relevant doses.[unreadable]