MicroRNAs as effectors of variable human drug metabolism
MicroRNA 作为可变人类药物代谢的效应器
基本信息
- 批准号:8653584
- 负责人:
- 金额:$ 28.61万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-08-01 至 2016-04-30
- 项目状态:已结题
- 来源:
- 关键词:3&apos Untranslated RegionsAddressAlgorithmsAllelesBilirubinBindingBioinformaticsBiological MarkersBiological ModelsBloodCell LineCellsClinicalCodeComplementDevelopmentDoseDrug usageEnzymesGene ExpressionGene Expression ProfileGenesGenetic PolymorphismGenomeGlucuronosyltransferaseGoalsHIVHIV InfectionsHepatocyteHumanIndiumIndividualLaboratoriesLeadLentivirus VectorLibrariesLiverLuciferasesMalignant NeoplasmsMessenger RNAMethodsMicroRNAsModelingMutagenesisMycophenolateOrganPatientsPharmaceutical PreparationsPharmacogeneticsPharmacogenomicsPhenotypePost-Transcriptional RegulationProteinsProteomeProteomicsRNA SequencesRNA SplicingRegulationReporterResponse ElementsRoleSafetySamplingSmall RNASubfamily lentivirinaeTestingTherapeutic IndexTimeUGT1A1 geneUntranslated RNAVariantWorkcell typecost effectivedrug metabolismfunctional genomicsgenetic variantin vivoirinotecanmRNA Expressionnovelnovel strategiesoverexpressionpreventresponsetranscription factortranscriptome sequencingtranscriptomics
项目摘要
DESCRIPTION (provided by applicant): The promise of pharmacogenomics - identification of the right dose of the right drug the first time for everyone - has yet to be fully realized in part
because we lack a complete understanding of the mechanisms underlying drug response variability. Recent studies suggest that microRNAs (miRs) - small noncoding RNAs that regulate gene expression post-transcriptionally - could be an important determinant of interindividual variability in drug metabolism and disposition. Here we propose to use a variety of novel approaches to identify miRs that are responsible for drug metabolizing enzyme variability. The focus of the application will be the UDP- glucuronosyltransferase (UGT) 1A enzymes that are critical to the elimination of many clinically important drugs with a narrow therapeutic index. Importantly, al 9 UGT1A enzymes (out of 18 total human UGTs) are encoded by spliced mRNAs that share an identical 3'-untranslated region (UTR). Although we have evidence that these enzymes are co-regulated by a post-transcriptional mechanism, virtually nothing is known regarding the role of miRs in UGT1A expression. Our overarching hypothesis is that specific miRs regulate UGT1A gene expression through the conserved UGT1A-3'-UTR mRNA region and/or indirectly by modulating regulatory transcription factor levels. To test this hypothesis, th following specific aims are proposed. In Aim 1 candidate miRs associated with UGT1A glucuronidation will be identified by multiple independent approaches, including bioinformatics, functional genomics screen, and whole genome (miR-transcriptome) association studies. The novel functional genomics screen we propose enables rapid identification of miRs that suppress a fluorescent- tagged miR 3'-UTR reporter from a pooled lentivirus library of all known human miRs. This method should have broad application outside of our field enabling a cost-effective rapid approach to describing of the "miR interactome". The reference UGT1A-3'-UTR allele will be evaluated as well as the major variant (*1b) associated with decreased bilirubin glucuronidation in vivo. miRs that are overexpressed in human liver bank samples with a low UGT1A activity and translational efficiency phenotype will also be identified by miR transcriptomics (arrays and Next gen small RNA-seq). In Aim 2 we wil confirm the functional impact of candidate miRs on UGT1A glucuronidation through overexpression (lenti-miRs) and knockdown (lenti- antagomiRs) of candidate miRs in human model cell lines and primary hepatocytes. In Aim 3 we will determine the mechanism of UGT1A regulation by functional miRs through use of UGT1A-3'UTR luciferase-reporter constructs and through studying effects of miR overexpression and knockdown in model cell lines and primary human hepatocytes on specific candidate transcription factor proteins (PXR and HNF1) as well as the entire proteome (iTRAQ LC-MS/MS method). This work will ultimately lead to development of validated predictive biomarkers (miR-associated polymorphisms and/or miR levels in blood) that would be incorporated into the pharmacogenetic algorithms currently being developed to guide dosing of low therapeutic index drugs.
描述(由申请人提供):药物基因组学的承诺——第一次为每个人确定正确剂量的药物——还没有完全实现
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Michael H Court其他文献
Assessment of cytochrome P450 induction in canine intestinal organoid models
犬肠道类器官模型中细胞色素 P450 诱导的评估
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:0
- 作者:
Itsuma Nagao;Meg Nakazawa;Takashi Goyama;Michael H Court;Yoko M. Ambrosini - 通讯作者:
Yoko M. Ambrosini
Abstracts presented at the World Congress of Veterinary Anaesthesiology, September 12–16, 2006, Santos, Brazil
- DOI:
10.1111/j.1467-2995.2007.00371a.x - 发表时间:
2007-07-01 - 期刊:
- 影响因子:
- 作者:
B Duncan X Lascelles;Michael H Court;Elizabeth M Hardie;Sheilah A Robertson - 通讯作者:
Sheilah A Robertson
Michael H Court的其他文献
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{{ truncateString('Michael H Court', 18)}}的其他基金
MicroRNAs as effectors of variable human drug metabolism
MicroRNA 作为可变人类药物代谢的效应器
- 批准号:
8514016 - 财政年份:2012
- 资助金额:
$ 28.61万 - 项目类别:
MicroRNAs as effectors of variable human drug metabolism
MicroRNA 作为可变人类药物代谢的效应器
- 批准号:
8574401 - 财政年份:2012
- 资助金额:
$ 28.61万 - 项目类别:
MicroRNAs as effectors of variable human drug metabolism
MicroRNA 作为可变人类药物代谢的效应器
- 批准号:
8341339 - 财政年份:2012
- 资助金额:
$ 28.61万 - 项目类别:
MicroRNAs as effectors of variable human drug metabolism
MicroRNA 作为可变人类药物代谢的效应器
- 批准号:
8827811 - 财政年份:2012
- 资助金额:
$ 28.61万 - 项目类别:
Mechanisms of adverse host responses to antibiotics
宿主对抗生素不良反应的机制
- 批准号:
7054675 - 财政年份:2005
- 资助金额:
$ 28.61万 - 项目类别:
Mechanisms of adverse host responses to antibiotics
宿主对抗生素不良反应的机制
- 批准号:
6925811 - 财政年份:2005
- 资助金额:
$ 28.61万 - 项目类别:
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