EXCEED THE SPACE PROVIDED. We hypothesize that the protective action of DHEA, in part, involves the modulation of the expression ofl cytochrome P450 monooxygenase(s) and/or other detoxification enzymes required for the bioactivation and disposition of chemicals through both Peroxisome Proliferator Activated Receptor Alpha dependent and independent pathways. Several studies have demonstrated that DHEA ameliorates environmental diseases at dosages lower than those required for DHEA-dependent peroxisome proliferation. 1. The goal of Specific Aim 1 is to establish whether metabolites of DHEA serve as proximal activators of PPAR or other nuclear receptors using cell-based reporter assays. We will test the ability of DHEA metabolites to activate PPARa, PXR, CAR, LXR, and FXR/BAR using reporter assays. 2. The goal of Specific Aim 2 is to test the hypothesis that 7a-hydroxy-DHEA and 7-oxo-DHEA are formed from DHEA in the hippocampus of rats and to characterize the gene regulation of these enzymes. The effect of DHEA treatment on levels of 7a-hydroxy- and 7-oxo-DHEA in the dentate gyrus region of hippocampus in rats will be determined. 3. The goal of Specific Aim 3 is to test the hypothesis that DHEA treatment activates PPAR by altering PPAR phosphorylation. Therefore, we will test the hypothesis that DHEA activates PPAR by affecting its phosphorylation status in rat hepatocytes and increases its action in transcription. 4. The goal of Specific Aim 4 is to test the hypothesis that the induction of Cyp3all in mouse liver by DI-IEA treatment is a PXR-dependent process. We will use PPARa and PXR-null mice to test the hypothesis that induction ofCyp3al 1 and other target genes by DHEA is PXR-dependent. 5. The goal of Specific Aim 5 is to test the hypothesis that DHEA induces gene expression through processes other than those mediated by PPARa and PXR. We will test changes in gene expression after DHEA treatment of wild-type, PPAR -null, and PXR-null mice using a mouse gene array to assess common pathways of regulation of these genes through PPAR, PXR, or unknown signaling pathways. PERFORMANCE SITE ========================================Section End===========================================
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