The objective of this project is to understand the mechanism of Ah receptor-mediated liver tumor promotion using the mouse as a model system. To accomplish this task, the investigators will attempt to unravel the mechanism by which a prototype chemical, 2,3,7,8-tetra-chlorodibenzo-p-dioxin ("dioxin"), acts as promoter of hepatocellular carcinoma in the two-stage model. The choice of dioxin is related to its biological potency and the large volume of genetic and pharmacological evidence that suggests its effects are mediated through a single ligand-activated transcription factor known as the Ah Receptor (AHR). Given the central nature of this signaling protein, efforts will be made to elucidate the molecular details of the dioxin-AHR pathway as it relates to liver tumor promotion. To this end, gene targeting will be used to manipulate various functional domains and expression patterns of the AHR, as well as its heterodimeric partner ARNT. The overall goal is to identify the signaling steps, transcriptional targets and cell types that are essential for dioxin-promoted hapatocarcinogenesis and receptor mediated hepatovascular development. To this end, the following specific aims are proposed.
Specific Aim 1 : Use conditional and null alleles to determine the cell types that participate in the promotional effects of dioxin.
Specific Aim 2 : Determine if the signal transduction of dioxin promotion is similar to AHR pathways that regulate xenobiotic metabolism and hepatovascular development.
Specific Aim 3 : Examine existing candidate genes for roles upstream of AHR-mediated tumor promotion.
Specific Aim 4 : Identify additional genes that are candidates for roles in AHR-mediated tumor promotion.
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