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dc.contributor.advisorKlaassen, Curtis D.
dc.contributor.authorCui, Yue
dc.date.accessioned2010-10-03T14:08:59Z
dc.date.available2010-10-03T14:08:59Z
dc.date.issued2010-07-29
dc.date.submitted2010
dc.identifier.otherhttp://dissertations.umi.com/ku:11097
dc.identifier.urihttp://hdl.handle.net/1808/6777
dc.description.abstractDespite the recent progress in understanding the expression patterns and regulatory mechanisms of drug-processing genes, namely phase-I and -II drug metabolizing enzymes and transporters in adults, very little is known of the alterations of these genes during liver development. Therefore, newborns and children are potentially at a higher risk of adverse drug reactions. The purpose of my dissertation is to characterize the expression and regulatory mechanisms of the drug-processing genes during postnatal liver maturation. The present study integrated various research technologies, including genetically-engineered mice, messenger RNA and protein assays, ChIP-on-chip, ChIP-Seq, transcription-factor binding assays, LC-MS/MS, and bioinformatics analysis. Cluster analysis demonstrated that the ontogenic expression of 82 drug-processing genes separate into 4 distinct patterns: perinatal enriched, early-adolescent enriched, late-adolescent enriched, and adult enriched. Critical nuclear receptors, including the xenobiotic sensor pregnane X receptor (PXR, N1I2), and the bile-acid sensor farnesoid X receptor (FXR, NR1H4), are crucial in regulating the expression of drug-processing genes during liver development. Initiation of bile-acid signaling, mediated largely via FXR, is a hallmark of the neonatal induction of major liver transporters involved in the enterohepatic circulation of bile acids, whereas PXR is more important for the induction of xenobiotic-processing genes in adolescent and adult period. Because the accessibility of transcription factors to the target genes is determined by chromatin epigenetic mechanisms, I have also determined the correlations between the expression of drug-processing genes and distinct chromatin epigenetic marks, and identified that histone H3 lysine 4 di-methylation (H3K4Me2) appeared to be the choice of nature to induce numerous drug-processing genes during postnatal liver development. In conclusion, in the present dissertation, I have performed a systemic characterization of critical drug-processing genes and transcription factors during postnatal liver maturation. I have demonstrated that the developmental regulation of drug metabolism and transport is a sequential event associated with changes of chromatin epigenetic signatures, which set a permissive environment for ligand-activated nuclear receptors to gain access to the target genes prior to transcription initiation. The current work has generated basic knowledge that will serve as a foundation for further understanding of pediatric pharmacology and toxicology in humans.
dc.format.extent321 pages
dc.language.isoen
dc.publisherUniversity of Kansas
dc.rightsThis item is protected by copyright and unless otherwise specified the copyright of this thesis/dissertation is held by the author.
dc.subjectHealth sciences
dc.subjectToxicology
dc.subjectPharmacology
dc.subjectMolecular biology
dc.subjectBile acids
dc.subjectDrug metabolism
dc.subjectEpigenetics
dc.subjectLiver development
dc.subjectNuclear receptors
dc.subjectTransporters
dc.titleDEVELOPMENTAL REGULATION OF THE DRUG-PROCESSING GENOME IN MOUSE LIVER
dc.typeDissertation
dc.contributor.cmtememberWan, Yu-Jui Yvonne
dc.contributor.cmtememberHagenbuch, Bruno
dc.contributor.cmtememberGuo, Grace
dc.contributor.cmtememberChristenson, Lane
dc.thesis.degreeDisciplinePharmacology, Toxicology & Therapeutics
dc.thesis.degreeLevelPh.D.
kusw.oastatusna
kusw.oapolicyThis item does not meet KU Open Access policy criteria.
kusw.bibid8085542
dc.rights.accessrightsopenAccess


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