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Pharmacogenetics of ADRs: Warfarin Toxicity

Pharmacogenetics of ADRs: Warfarin Toxicity
ADR 的药物遗传学:华法林毒性
批准号:
7531761
负责人:
Allan Edward Rettie
金额:
$39.48万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2004
资助国家:
美国
项目状态:
已结题
起止时间:
2004-04-01 至 2011-07-31
关键词:
4-HydroxycoumarinsAccident and Emergency departmentActive SitesAddressAdherenceAdmission activityAdverse effectsAdverse eventAdverse reactionsAffectAmericanAnticoagulant therapyAnticoagulantsAnticoagulationBindingBinding SitesBiological AssayCYP2C9 geneClassificationClinical ResearchCoagulation Factor DeficiencyComplementary DNAContractsCoumarinsCytochrome P450DNA-Binding ProteinsDNA-Protein InteractionDevelopmentDistalDoseDropsDrug InteractionsDrug toxicityElementsEnzyme InhibitionEnzymesEquilibriumEtiologyEventFood-Drug InteractionsFundingGenesGeneticGenetic PolymorphismGenetic VariationGoalsGrantGreen SHaplotypesHemorrhageHepaticHospitalsHumanHuman GeneticsHydroxylationIndividualIntegration Host FactorsInternational Normalized RatioKnowledgeLigandsLightLiteratureLiverLiver MicrosomesLuciferasesMedicineMembraneMembrane ProteinsMetabolic ControlMethodologyModelingMolecularMolecular BiologyMutationNQ-2-OHNatureOralOutpatientsPatientsPharmaceutical PreparationsPharmacodynamicsPharmacogeneticsPhasePhotoaffinity LabelsPreparationPriceProteinsPublic HealthReactionRecombinantsRecordsRecoveryRegulationRegulatory ElementReporterReportingResearchResearch PersonnelResearch ProposalsResistanceRiskRoleScheduleSiteSite-Directed MutagenesisSourceStructural ModelsStructure-Activity RelationshipTechniquesTherapeutic IndexTimeTimeLineToxic effectTrager Psychophysical IntegrationTranscriptional RegulationUniversitiesVariantVisitVitamin KWarfarinWashingtonWestern WorldWisconsinWorkalpha benzopyronecompliance behaviordesignenantiomergene interactionimprovedindanedionemedical schoolsmembrane modelmutantnational surveillancenovelperformance sitepromoterprospectiveprotein structure predictionreceptorresponsevitamin K epoxide reductase

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中文摘要
翻译
这项研究的长期目标是了解人类基因变异是如何发生的
英文摘要
The long-term aim of this research is to understand how human genetic variation influences drug toxicity. In this renewal application, we will continue our efforts to elucidate mechanisms underlying adverse drug reactions to oral anticoagulants, specifically the coumarin drug, warfarin, which is taken daily by over 2 million Americans, and remains one of the most common causes of emergency room visits because of adverse reactions. In the previous funding period the focus was primarily on genetic variation within the cytochrome P450 enzyme, CYP2C9, because it controls metabolic clearance of the more potent (S) enantiomer of the racemic drug. However, during the previous granting period the gene for the warfarin target protein - VKORC1 - was cloned and has become the new focus of this application because it controls the pharmacodynamic response to the drug. In the present application we are attempting to understand; 1) regulatory mechanisms that influence vitamin K epoxide reductase (VKOR) hepatic expression and, 2) the fundamental nature of the warfarin binding site(s) in VKOR. To address these goals we have formulated the following aims: Specific Aim 1: Determine the functional significance of regulatory (promoter and intronic) polymorphisms at the VKORC1 locus using reporter constructs, site-directed mutagenesis and DNA/protein binding assays. Specific Aim 2: Define structure-activity relationships at the level of both the ligand and the protein for reversible and irreversible inhibition of VKOR using a set of structurally diverse vitamin K antagonists together with novel modeling of this membrane-bound enzyme. Due to the broad scope of the proposed research, this proposal brings together investigators at performance sites in Seattle and Milwaukee to work on these problems. Successful completion of these studies will add to our knowledge of the fundamental mechanisms by which; (i) polymorphisms in the VKORC1 gene affect patient dosing with warfarin and (ii) the vitamin K cycle is inhibited by warfarin.
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New Vistas in Vitamin K Metabolism
  • 批准号:
    8477918
  • 项目类别:
  • 资助金额:
    $28.77万
  • 财政年份:
    2013
  • 负责人:
    Allan Edward Rettie
  • 依托单位:
New Vistas in Vitamin K Metabolism
  • 批准号:
    9031119
  • 项目类别:
  • 资助金额:
    $28.63万
  • 财政年份:
    2013
  • 负责人:
    Allan Edward Rettie
  • 依托单位:
Genotype-Dependent Drug Interactions
  • 批准号:
    8380462
  • 项目类别:
  • 资助金额:
    $44.86万
  • 财政年份:
    2012
  • 负责人:
    Allan Edward Rettie
  • 依托单位:
Genotype-Dependent Drug Interactions
  • 批准号:
    8334083
  • 项目类别:
  • 资助金额:
    $36.13万
  • 财政年份:
    2011
  • 负责人:
    Allan Edward Rettie
  • 依托单位: