Mechanisms for modulation of miRNA-mediated gene silencing
miRNA 介导的基因沉默的调节机制
基本信息
- 批准号:10264067
- 负责人:
- 金额:$ 34.07万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:3&apos Untranslated RegionsAdultAffectAffinity ChromatographyAmino Acid SequenceAstrocytesBindingBinding ProteinsBinding SitesBiological AssayBrainCRISPR/Cas technologyCell Differentiation processCell LineCell ShapeCellsComplexDevelopmentDiseaseElementsEngineeringEukaryotic CellExhibitsGene ExpressionGene Expression RegulationGene SilencingGoalsHeterogeneityHomeostasisHumanImmunoprecipitationIn VitroIndividualInvestigationKnowledgeLibrariesMeasuresMediatingMessenger RNAMicroRNAsModelingMolecularMusMutateNervous system structureNeuronal DifferentiationNeuronsOrganismOutcomePeptide Initiation FactorsPhasePlayPolyribosomesPositioning AttributePost-Transcriptional RegulationPredispositionRNA BindingRNA HelicaseRNA-Binding ProteinsRNA-Induced Silencing ComplexRNA-Protein InteractionReporterRepressionRibosomesRoleScanningShapesStructureSystemTestingTranscriptTranslatingTranslation InitiationTranslational RepressionTranslationsUntranslated RNAVariantWorkbrain cellcell typecombinatorialexperimental studyhelicasehuman diseasein vivoinhibitor/antagonistmRNA Decaynerve stem cellpostnataltissue culture
项目摘要
Abstract
In eukaryotic cells, gene expression is regulated at multiple levels. Post-transcriptional regulation is, in part,
mediated by micro RNAs (miRNAs), which act within the miRNA-induced silencing complex (miRISC).
However, susceptibility of mRNAs to miRNA-mediated silencing appears to depend on the cell type and on the
features of mRNA target itself. Our recent studies indicate that the stability and translation efficiency of miRNA-
targeted mRNAs are determined by interactions between miRISC and RNA-binding proteins (RBPs). In this
proposal, we seek to elucidate the basic mechanism of miRISC-mediated translational repression and
its modulation by RBPs and target mRNAs, in a cell-type-specific manner. In Aim 1, we intend to
determine how miRNAs, as part of the miRISC, repress translation during the initiation phase. Specifically, we
will seek to determine the role of eIF4A helicase and the eIF4F complex in miRNA-mediated translational
repression during translation initiation and 43S ribosome scanning. To achieve this goal we will use massively
parallel reporter assays (MPRA), CRISPR/Cas-9 engineered cells, and translation inhibitors. We will use the
same approach to analyze the mechanism through which Pumilio and AU-rich (ARE) binding sites affect
miRNA-mediated translational repression. In Aim 2, we will ascertain how AU-rich motifs modulate miRNA-
mediated repression of target mRNAs. Specifically, we will determine the mechanism by which AREs and
ARE-binding proteins (ARE-BPs) can up- or down-regulate miRNA-mediated gene silencing in a cell-specific
manner. Lastly, we will use immunoprecipitation of ARE-BPs and target mRNA and test interaction between
miRISC, ARE-BPs, and mRNA, to determine how ARE-BPs' binding to target mRNAs in a positionally biased
manner interferes with mRISC-mRNA target interaction to modulate gene regulation. In Aim 3, we will
elucidate how modulation of miRNA-mediated gene silencing by RBPs shapes the differentiation of mouse
neurons and results in cell-specific effects distinguishing neurons and astrocytes in the mature CNS.
Specifically, we will analyze individual and combinatorial effects of miRNAs and RBPs using reporter libraries,
endogenous mRNAs, polysome profile analyses, and translating ribosome affinity purification (TRAP) to
evaluate specialization of gene expression in murine brain cell types. Our central hypothesis is that cell-type-
specific interactions between the target mRNAs, RBPs, and miRISC determine the extent of miRNA-mediated
translational repression and mRNA decay. Our long-term goal is to define how miRNA-mediated gene
expression control is established in a cell-type-specific manner by modulation of RBPs and features of target
mRNAs. The nervous system, with an exquisite heterogeneity of cells, represents a great structure to test our
hypotheses. Together, these experiments will reveal why specific mRNAs respond robustly to miRISC while
others do not, and how the modulation of miRNA–mediated gene silencing is established in a cell-specific
manner by the activity and presence of RBPs as well as sequence features of target mRNAs.
摘要
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Sergej Djuranovic其他文献
Sergej Djuranovic的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Sergej Djuranovic', 18)}}的其他基金
Dissecting mRNA-ribosome interaction in AU-rich transcriptome of Plasmodium falciparum
解析恶性疟原虫富含 AU 的转录组中 mRNA-核糖体相互作用
- 批准号:
10590725 - 财政年份:2021
- 资助金额:
$ 34.07万 - 项目类别:
Dissecting mRNA-ribosome interaction in AU-rich transcriptome of Plasmodium falciparum
解析恶性疟原虫富含 AU 的转录组中 mRNA-核糖体相互作用
- 批准号:
10415144 - 财政年份:2021
- 资助金额:
$ 34.07万 - 项目类别:
Dissecting mRNA-ribosome interaction in AU-rich transcriptome of Plasmodium falciparum
解析恶性疟原虫富含 AU 的转录组中 mRNA-核糖体相互作用
- 批准号:
10798664 - 财政年份:2021
- 资助金额:
$ 34.07万 - 项目类别:
Dissecting mRNA-ribosome interaction in AU-rich transcriptome of Plasmodium falciparum
解析恶性疟原虫富含 AU 的转录组中 mRNA-核糖体相互作用
- 批准号:
10210799 - 财政年份:2021
- 资助金额:
$ 34.07万 - 项目类别:
Mechanisms for modulation of miRNA-mediated gene silencing
miRNA 介导的基因沉默的调节机制
- 批准号:
10387979 - 财政年份:2015
- 资助金额:
$ 34.07万 - 项目类别:
Mechanisms for modulation of miRNA-mediated gene silencing
miRNA 介导的基因沉默的调节机制
- 批准号:
10674772 - 财政年份:2015
- 资助金额:
$ 34.07万 - 项目类别:
MECHANISMS FOR MODULATION OF MIRNA-MEDIATED GENE SILENCING
miRNA 介导的基因沉默的调节机制
- 批准号:
9132318 - 财政年份:2015
- 资助金额:
$ 34.07万 - 项目类别:
Mechanisms for modulation of miRNA-mediated gene silencing
miRNA 介导的基因沉默的调节机制
- 批准号:
10461076 - 财政年份:2015
- 资助金额:
$ 34.07万 - 项目类别:
相似海外基金
Impact of alternative polyadenylation of 3'-untranslated regions in the PI3K/AKT cascade on microRNA
PI3K/AKT 级联中 3-非翻译区的替代多聚腺苷酸化对 microRNA 的影响
- 批准号:
573541-2022 - 财政年份:2022
- 资助金额:
$ 34.07万 - 项目类别:
University Undergraduate Student Research Awards
How do untranslated regions of cannabinoid receptor type 1 mRNA determine receptor subcellular localisation and function?
1 型大麻素受体 mRNA 的非翻译区如何决定受体亚细胞定位和功能?
- 批准号:
2744317 - 财政年份:2022
- 资助金额:
$ 34.07万 - 项目类别:
Studentship
MICA:Synthetic untranslated regions for direct delivery of therapeutic mRNAs
MICA:用于直接递送治疗性 mRNA 的合成非翻译区
- 批准号:
MR/V010948/1 - 财政年份:2021
- 资助金额:
$ 34.07万 - 项目类别:
Research Grant
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
- 批准号:
10019570 - 财政年份:2019
- 资助金额:
$ 34.07万 - 项目类别:
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
- 批准号:
10223370 - 财政年份:2019
- 资助金额:
$ 34.07万 - 项目类别:
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
- 批准号:
10455108 - 财政年份:2019
- 资助金额:
$ 34.07万 - 项目类别:
Synergistic microRNA-binding sites, and 3' untranslated regions: a dialogue of silence
协同的 microRNA 结合位点和 3 非翻译区:沉默的对话
- 批准号:
255762 - 财政年份:2012
- 资助金额:
$ 34.07万 - 项目类别:
Operating Grants
Analysis of long untranslated regions in Nipah virus genome
尼帕病毒基因组长非翻译区分析
- 批准号:
20790351 - 财政年份:2008
- 资助金额:
$ 34.07万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
Search for mRNA elements involved in the compatibility between 5' untranslated regions and coding regions in chloroplast translation
寻找参与叶绿体翻译中 5 非翻译区和编码区之间兼容性的 mRNA 元件
- 批准号:
19370021 - 财政年份:2007
- 资助金额:
$ 34.07万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Post-transcriptional Regulation of PPAR-g Expression by 5'-Untranslated Regions
5-非翻译区对 PPAR-g 表达的转录后调控
- 批准号:
7131841 - 财政年份:2006
- 资助金额:
$ 34.07万 - 项目类别: