MicroRNA Biogenesis and the Cancer Proteome
MicroRNA 生物发生和癌症蛋白质组
基本信息
- 批准号:7431456
- 负责人:
- 金额:$ 262.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-09-30 至 2012-08-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAcidsActinsAddressAffectAffinityAgreementAlgorithmsAnabolismAnecdotesAnimalsApoptosisAreaAttentionAwardBehaviorBibliographyBindingBiogenesisBioinformaticsBiologicalBiological AssayBiological ProcessBiomedical ComputingBiostatistical MethodsBiotinBrainBrain GlioblastomaBrain NeoplasmsBreastCamptothecinCancer BiologyCancer ModelCancer PatientCancer SurvivorshipCaringCaspaseCategoriesCationsCell CycleCell Cycle ProgressionCell DeathCell Differentiation processCell LineCell ProliferationCellsCellular AssayCellular biologyCessation of lifeCharacteristicsChemicalsChromatographyChromosome PairingCleaved cellClinicClinicalClinical DataClinical ResearchCluster AnalysisCodeCollaborationsColorComplexComputer softwareComputersConditionControl AnimalCore FacilityCoupledCreativenessCyclic AMP-Dependent Protein KinasesCyclin-Dependent KinasesCyclotronsDICER1 geneDNADNA DamageDNA IntegrationDNA SequenceDNA analysisDataData AnalysesData SetDefectDevelopmentDisease regressionDisruptionDistressDoctor of PhilosophyDown-RegulationDyesElementsEmbryoExhibitsFailureFamilyFigs - dietaryFosteringFourier TransformFreezingFrequenciesFunctional RNAGene ClusterGene ExpressionGene MutationGene OrderGenesGeneticGenetsGenomeGenome MappingsGenomicsGlioblastomaGliomaGlutamatesGrowthGuidelinesHDAC1 geneHematoxylin and Eosin Staining MethodHeterogeneityHistologyHospital RecordsHospitalsHumanHuman ResourcesImmigrationImplantIn VitroIndividualInstitutionIonsIsotopesIsotopically-Coded Affinity TaggingJournalsKolmogorov-Smirnov TestLabelLaboratoriesLeadLightLiquid ChromatographyLocationLungMalignant NeoplasmsMalignant neoplasm of brainMalignant neoplasm of lungManuscriptsMass Spectrum AnalysisMeasurementMeasuresMediatingMentorsMessenger RNAMetabolicMethodologyMethodsMethylationMicroRNAsMicroarray AnalysisMitogensModelingMolecularMolecular ProfilingMolecular and Cellular BiologyMusMutationNational Cancer InstituteNatureNervous system structureNeurobiologyNeuronsNeurosurgeonNormal CellNumbersOncogenesOperative Surgical ProceduresOutcomeOutputOvarianPDGFRA genePaperPathway AnalysisPathway interactionsPatientsPatternPeptidesPhysical Map of the Human GenomePlayPolymerase Chain ReactionPositioning AttributePrimary NeoplasmProbabilityProcessProductionProtein OverexpressionProteinsProteomeProteomicsProtocols documentationPublishingRLK5-associated protein phosphataseRNARNA Polymerase IIIRNA SplicingRNA analysisRangeRateRattusRecording of previous eventsRegression AnalysisRegulationRelative (related person)ReportingResearchResearch Ethics CommitteesResearch PersonnelResidenciesResolutionResourcesRoleSamplingScanningScienceScientistSeminalSignal PathwaySignal TransductionSkinSlideSolidSourceSpecificitySpecimenSpottingsStagingStudentsSubfamily lentivirinaeSubgroupSurvival AnalysisSynapsesSystemTP53 geneTechniquesTechnologyTestingTimeTissue BanksTissue ExtractsTissue SampleTissuesTrainingTranslational ResearchTranslationsTrypsinTumor Suppressor ProteinsTumor TissueTumorigenicityUniversitiesUp-RegulationValidationWashingtonWeekWestern BlottingWidthWomanWorkabstractinganimal carebasecancer cellcancer genomecarcinogenesiscareercell growthcell motilitycellular transductionclinically relevantcomparativecyanine dye 5cyclin-dependent kinase 6densityfight againstfollow-upforgingfrontierfunctional genomicsgenome-wide analysishazardhuman DICER1 proteinhuman subjectimprovedin vitro Assayin vitro Modelin vivoinnovationinsightinterestmRNA ExpressionmRNA Stabilitymass spectrometermedical schoolsmembermetaplastic cell transformationmouse modelneoplastic cellneuron apoptosisneuron lossneurosurgerynovelnovel therapeuticsoutcome forecastperipheral bloodphysical mappingpostnatalprogramsprotein expressionresearch studyresponsereversed phase chromatographysizesmall hairpin RNAstatisticssuccesssynthetic proteintherapeutic targettherapy outcometooltumortumorigenesisvectorvector controlwillingness
项目摘要
Recent studies in human cancers have revealed defects in microRNA biogenesis that promote
tumor aggressiveness and decrease survival via mechanisms that are poorly understood. Much of
the control of protein expression by microRNAs occurs without alterations in mRNA expression, and
single microRNAs may target dozens of mRNAs in a tissue specific manner. Thus, this broad-based
decrease in microRNA synthesis presents a challenge to those trying to understand its downstream
molecular effects on carcinogenesis. Here we propose a new strategy that will comprehensively
identify the mechanisms by which defects in microRNA biogenesis decrease cancer survivorship.
This approach involves the integration of genome-scale high throughput quantitative mass
spectrometry analysis of the cancer proteome with genome-wide microRNA, mRNA and DNA
analyses of human brain tumors (glioblastomas) that have intact or defective microRNA biogenesis.
Novel algorithms that incorporate clinical variables will be used to generate an integrated genome-
scale view of identified differences, and clinically-related targets will be investigated further using in
vivo and in vitro models. Preliminary studies in our laboratory using aCGH and mRNA microarrays
revealed deletion at the DICER1 locus and decreased DICER1 mRNA expression in a subset of
glioblastomas, and this correlated with decreased microRNA expression and survival. Genome-
wide analysis identified numerous microRNAs that were differentially expressed between
glioblastomas with low versus high DICER1 expression. Cdk6, which promotes cell cycle
progression, was a predicted target of several of these microRNAs. DICER1 knockdown in
glioblastoma cells increased cell growth and upregulated Cdk6 protein expression. Importantly,
Cdk6 protein was overexpressed in glioblastomas with low DICER1 expression, suggesting that
Cdk6 upregulation may be one mechanism by which defective microRNA biogenesis contributes to
increased tumor aggressiveness. This innovative and ambitious project will integrate mass
spectrometry proteomics, genomics and clinical variables to comprehensively identify the
mechanisms underlying the decreased cancer survivorship associated with dysregulated microRNA
biogenesis.
最近对人类癌症的研究发现,促进肿瘤发生的microRNA生物发生存在缺陷
肿瘤的侵袭性和通过鲜为人知的机制降低存活率。大部分
通过microRNAs控制蛋白质的表达而不改变mRNA的表达,并且
单个microRNAs可能以组织特异性的方式靶向数十个mRNAs。因此,这个基础广泛的
MicroRNA合成的减少给那些试图了解其下游的人带来了挑战
癌症发生的分子效应。在这里,我们提出了一项新的战略,将全面
确定microRNA生物发生缺陷降低癌症存活率的机制。
该方法涉及基因组规模的高通量定量质量的整合
全基因组microRNA、mRNA和DNA对肿瘤蛋白质组的光谱分析
分析具有完整或缺陷microRNA生物发生的人脑肿瘤(胶质母细胞瘤)。
结合临床变量的新算法将被用来生成完整的基因组-
已识别的差异和临床相关靶点的比例视图将使用
体内模型和体外模型。我们实验室应用aCGH和mRNA微阵列的初步研究
发现DICER1基因缺失并降低了DICER1基因的表达
胶质母细胞瘤,这与microRNA表达减少和存活率相关。基因组-
广泛的分析发现了大量差异表达的microRNA
DICER1低表达与高表达的胶质母细胞瘤。促进细胞周期的CDK6
进展,是这些microRNA中的几个预测的目标。DICER1击倒在
胶质母细胞瘤细胞促进细胞生长,上调CDK6蛋白表达。重要的是
CDK6蛋白在DICER1低表达的胶质母细胞瘤中高表达,提示
CDK6上调可能是microRNA生物发生缺陷导致
肿瘤侵袭性增加。这一创新和雄心勃勃的项目将把群众
光谱蛋白质组学、基因组学和临床变量综合鉴定
与调节失调的microRNA相关的癌症存活率下降的机制
生物发生学。
项目成果
期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Alternative splicing of CHEK2 and codeletion with NF2 promote chromosomal instability in meningioma.
CHEK2 的选择性剪接以及与 NF2 的共缺失会促进脑膜瘤中的染色体不稳定。
- DOI:10.1593/neo.111574
- 发表时间:2012
- 期刊:
- 影响因子:0
- 作者:Yang,HongWei;Kim,Tae-Min;Song,SydneyS;Shrinath,Nihal;Park,Richard;Kalamarides,Michel;Park,PeterJ;Black,PeterM;Carroll,RonaS;Johnson,MarkD
- 通讯作者:Johnson,MarkD
Functional genomic analysis of chromosomal aberrations in a compendium of 8000 cancer genomes.
- DOI:10.1101/gr.140301.112
- 发表时间:2013-02
- 期刊:
- 影响因子:7
- 作者:Kim TM;Xi R;Luquette LJ;Park RW;Johnson MD;Park PJ
- 通讯作者:Park PJ
A small subunit processome protein promotes cancer by altering translation.
一种小亚基加工蛋白通过改变翻译来促进癌症。
- DOI:10.1038/onc.2014.376
- 发表时间:2015
- 期刊:
- 影响因子:8
- 作者:Yang,HW;Kim,T-M;Song,SS;Menon,L;Jiang,X;Huang,W;Black,PM;Park,PJ;Carroll,RS;Johnson,MD
- 通讯作者:Johnson,MD
Numb regulates glioma stem cell fate and growth by altering epidermal growth factor receptor and Skp1-Cullin-F-box ubiquitin ligase activity.
- DOI:10.1002/stem.1120
- 发表时间:2012-07
- 期刊:
- 影响因子:5.2
- 作者:Jiang, Xiuli;Xing, Hongyan;Kim, Tae-Min;Jung, Yuchae;Huang, Wei;Yang, Hong Wei;Song, Shengye;Park, Peter J.;Carroll, Rona S.;Johnson, Mark D.
- 通讯作者:Johnson, Mark D.
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MARK D JOHNSON其他文献
MARK D JOHNSON的其他文献
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{{ truncateString('MARK D JOHNSON', 18)}}的其他基金
Preventing Glioma Cancer Stem Cell Dispersal Using Cdc2 Kinase Inhibitors
使用 Cdc2 激酶抑制剂预防神经胶质瘤干细胞扩散
- 批准号:
8018590 - 财政年份:2010
- 资助金额:
$ 262.5万 - 项目类别:
Preventing Glioma Cancer Stem Cell Dispersal Using Cdc2 Kinase Inhibitors
使用 Cdc2 激酶抑制剂预防神经胶质瘤干细胞扩散
- 批准号:
8605935 - 财政年份:2010
- 资助金额:
$ 262.5万 - 项目类别:
Preventing Glioma Cancer Stem Cell Dispersal Using Cdc2 Kinase Inhibitors
使用 Cdc2 激酶抑制剂预防神经胶质瘤干细胞扩散
- 批准号:
8213710 - 财政年份:2010
- 资助金额:
$ 262.5万 - 项目类别:
Preventing Glioma Cancer Stem Cell Dispersal Using Cdc2 Kinase Inhibitors
使用 Cdc2 激酶抑制剂预防神经胶质瘤干细胞扩散
- 批准号:
8415876 - 财政年份:2010
- 资助金额:
$ 262.5万 - 项目类别:
Preventing Glioma Cancer Stem Cell Dispersal Using Cdc2 Kinase Inhibitors
使用 Cdc2 激酶抑制剂预防神经胶质瘤干细胞扩散
- 批准号:
7792679 - 财政年份:2010
- 资助金额:
$ 262.5万 - 项目类别:
Genomics/Proteomics of p53-mediated Neuronal Death
p53 介导的神经元死亡的基因组学/蛋白质组学
- 批准号:
7173349 - 财政年份:2003
- 资助金额:
$ 262.5万 - 项目类别:
Genomics/Proteomics of p53-mediated Neuronal Death
p53 介导的神经元死亡的基因组学/蛋白质组学
- 批准号:
6466242 - 财政年份:2003
- 资助金额:
$ 262.5万 - 项目类别:
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