This proposal is directed at understanding the toxicology of halogenated dibenzo-p-dioxins (""""""""dioxins""""""""), as well as the biology of a basic-helix-loop-helix-PAS (bHLH-PAS) protein known as the Ah receptor (AHR). The goal is to better understand the biology of a number of modifiers of AHR signal transduction. The specific questions that will be answered are whether any of these modifiers play a role in dioxin toxicity or if their activity is limited to the induction of xenobiotic metabolizing enzymes (XMEs). The factors to be examined include the small immunophilin-like molecule we refer to as ARA9, a novel homologue of the Drosophila kelch protein, referred to as ARA3, and members of the nonreceptor tyrosine kinase superfamily, cYes and cSrc. The other modifiers to be included in these screens are members of the bHLH-PAS superfamily. These include the dominant negative """"""""Ah receptor related"""""""" protein (AHRR), the steroid receptor coactivator (SRC-1), and the AHR partners, ARNT and ARNT2. The final putative modifier we will examine is a cis-acting intragenic element we have recently identified within the AHR's structural gene. We propose that this element regulates AHR expression and thus may be a modulator of cellular sensitivity to receptor agonists. By monitoring toxic endpoints, in parallel with XME induction and liver development, we will be able to identify factors that are shared by these three processes and those which are specific to only a subset of pathways. Identification of pathway-specific factors will provide insight into the molecular mechanisms that underlie each of these biological processes. Information from these studies will have a significant impact on how we estimate risk from chemicals like dioxin, either by providing support for the use of XME induction as a surrogate for toxicity or an argument against such a paradigm.
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