Cellular Roles in Liver Pathology: Dioxin as Prototype

University Of Wisconsin-Madison, Madison WI

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Abstract

DESCRIPTION (provided by applicant): This is a proposal to understand Ah receptor (AHR) biology and also an attempt to develop new tools for the toxicologist. In this proposal, we will couple recombinant mouse models, liver cell isolation techniques and modern genomic technology to identify those transcriptional outputs that define the AHR's role in the hepatotoxic effects of potent agonists like 2,3,7,8-tetrachlorodibenzo-pdioxin ("dioxin"). In parallel, we will use the AHR as a model system to develop a new generation of tools, reagents and resources that will aid biologists in their efforts to understand toxicant action. Our specific aims are: Aim 1: Develop cDNA clone sets and microarray technologies (MAT) that are optimal for the study of AHR signaling in parenchymal and nonparenchymal cell types. Aim 2: Develop statistical tools for the optimal design of toxicogenomics studies, as well as to interpret these studies by incorporating data from mutant animal models, pathology and the biomedical literature. Aim 3: We will test the hypothesis that various cell types are interacting and that this interaction can be detected through the presentation of waves of temporally linked transcriptional change. Aim 4: Elucidate the roles of the candidate genes, AHR, Cyplal, Cypla2, Cyplbl, TNF-a and IL6. Using recombinant mouse models, each of these genes will be tested for roles in aspects of hepatotoxicity or for roles in dioxin-induced signaling across hepatic cell types. Aim 5: Test the idea that global aberrations in gene expression can serve as a new definition of toxicity. We will also test the idea that patterns of gene expression will define various pathologies. Aim 6: The MAT we develop will have significant application across toxicant classes. Therefore, we will develop a resource where toxicologists can view the transcriptional responses to dioxin and classic hepatotoxicants.