Molecular mechanisms of translational regulation in aging
衰老转化调控的分子机制
基本信息
- 批准号:9902274
- 负责人:
- 金额:$ 56.04万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-04-01 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAgeAgingAmino AcidsApplications GrantsBayesian ModelingBindingBinding SitesBiological AssayBiological ModelsCandidate Disease GeneCardiovascular DiseasesCellsChimeric ProteinsDataDevelopmentDietary InterventionDiseaseElementsEngineeringFluorescence MicroscopyFunctional disorderGene DeletionGene ExpressionGene Expression RegulationGenerationsGenesGeneticGenetic EpistasisGenetic TranscriptionGenetic TranslationGoalsInvertebratesKnowledgeLinkLongevityMalignant NeoplasmsMammalsMapsMediatingMessenger RNAModelingMolecularMonitorMothersMutationNerve DegenerationNon-Insulin-Dependent Diabetes MellitusNutrientOrganismOther GeneticsPathway interactionsPatternPlayPost-Transcriptional RegulationProcessProtein BiosynthesisProteinsRNARNA-Binding ProteinsRegulationRegulatory ElementReporterRoleSignal PathwayStarvationSystemSystems BiologyTestingTimeTranscriptional RegulationTranslatingTranslational RegulationTranslationsYeastsagedbioinformatics toolcell agedietary restrictiondifferential expressionexperimental studyflygene therapygenetic regulatory proteingenome wide screengenome-widehealthspanimprovedin vivoinsightintervention effectmicrofluidic technologymutantnext generation sequencingprogramsresponseribosome profilingtranscription factortranscriptome sequencing
项目摘要
Molecular mechanisms of translational regulation in aging
Genome-wide microarray and RNA sequencing studies have revealed changes in the expression of hundreds
of genes during aging in diverse organisms. Transcriptional regulation plays an important role in the control of
gene expression during aging; however, translation efficiency likely plays an equally important role in determining
protein abundance, but has been understudied in this context. Here we propose to study translational changes
that are associated with increased longevity induced by dietary and genetic interventions and examine the mech-
anisms of post-transcriptional gene regulation in aging using yeast as a model system. We will test the hypoth-
esis that, in response to dietary restriction (DR) and genetic alterations that extend lifespan, mRNA-binding pro-
teins (RBPs) coordinately regulate diverse cytoprotective genes by affecting their translation efficiency. To iden-
tify RBPs involved in regulation of these processes, we will apply RNA-Seq and ribosome profiling combined
with next-generation sequencing and characterize transcriptional and translational changes in replicatively aged
yeast cells in response to DR and in a panel of long-lived gene deletion mutants identified in genome-wide
screens. Using the Bayesian network modeling approach, we will integrate transcriptional and translational pro-
filing data with information about transcription factor (TF) binding sites and sequence elements recognized by
RBPs and build a regulatory interaction network. We will then characterize RBPs and directly identify their
mRNA-binding targets. These data will allow us to uncover specific mechanisms and identify cis-regulatory ele-
ments that are responsible for the translational signatures associated with increased longevity. We will also
utilize fluorescence microscopy and cutting-edge microfluidic technologies in order to monitor how the abun-
dance of RBPs changes with age at the single-cell level. Finally, we will use reverse engineering approach to
test if the regulators identified using our systems approach play a causative role in mediating the lifespan exten-
sion through genetic epistasis experiments. Successful completion of this study will add valuable insight into
fundamental principles of translational regulation, and may provide a better understanding of the molecular
mechanisms of aging and lifespan control.
衰老中翻译调控的分子机制
全基因组微阵列和RNA测序研究揭示了数百种基因表达的变化,
基因在不同生物体衰老过程中的变化。转录调控在调控细胞凋亡中起着重要作用。
衰老过程中的基因表达;然而,翻译效率可能在决定衰老过程中起着同样重要的作用。
蛋白质丰度,但在这方面研究不足。在这里,我们建议研究翻译的变化
与饮食和遗传干预引起的长寿有关,并检查了这种机制,
使用酵母作为模型系统的衰老中转录后基因调控的anisms。我们将检验这个假设-
研究表明,作为对饮食限制(DR)和延长寿命的遗传改变的反应,
蛋白质(RBP)通过影响其翻译效率来协调调节多种细胞保护基因。去确认-
为了验证参与这些过程调控的RBP,我们将结合RNA-Seq和核糖体分析,
与下一代测序和表征转录和翻译的变化,
酵母细胞对DR的反应,以及在全基因组中鉴定的一组长寿基因缺失突变体中,
卡位使用贝叶斯网络建模方法,我们将整合转录和翻译前,
用转录因子(TF)结合位点和序列元件的信息归档数据,
限制性商业惯例和建立监管互动网络。然后,我们将描述限制性商业惯例,并直接确定其
mRNA结合靶点。这些数据将使我们能够揭示特定的机制,并确定顺式调节元件。
负责与寿命增加相关的翻译签名的片段。我们还将
利用荧光显微镜和尖端的微流体技术,以监测如何abun-
在单细胞水平上,RBP的舞蹈随年龄而变化。最后,我们将使用逆向工程的方法,
测试使用我们的系统方法确定的调节因子是否在介导寿命延长中发挥因果作用,
锡永遗传上位性实验。成功完成这项研究将增加宝贵的见解,
翻译调控的基本原则,并可能提供更好的理解的分子
衰老和寿命控制的机制。
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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Vyacheslav M Labunskyy其他文献
Vyacheslav M Labunskyy的其他文献
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{{ truncateString('Vyacheslav M Labunskyy', 18)}}的其他基金
Molecular mechanisms of translational regulation in aging
衰老转化调控的分子机制
- 批准号:
10552685 - 财政年份:2019
- 资助金额:
$ 56.04万 - 项目类别:
Molecular mechanisms of translational regulation in aging
衰老转化调控的分子机制
- 批准号:
10341158 - 财政年份:2019
- 资助金额:
$ 56.04万 - 项目类别:
Molecular mechanisms of translational regulation in aging
衰老转化调控的分子机制
- 批准号:
9564583 - 财政年份:2017
- 资助金额:
$ 56.04万 - 项目类别:
Endoplasmic Reticulum Thiol Redox State and Unfolded Protein Response in Aging
衰老过程中内质网硫醇氧化还原状态和未折叠蛋白反应
- 批准号:
8384660 - 财政年份:2012
- 资助金额:
$ 56.04万 - 项目类别:
Endoplasmic Reticulum Thiol Redox State and Unfolded Protein Response in Aging
衰老过程中内质网硫醇氧化还原状态和未折叠蛋白反应
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8549048 - 财政年份:2012
- 资助金额:
$ 56.04万 - 项目类别:
Endoplasmic Reticulum Thiol Redox State and Unfolded Protein Response in Aging
衰老过程中内质网硫醇氧化还原状态和未折叠蛋白反应
- 批准号:
8918824 - 财政年份:2012
- 资助金额:
$ 56.04万 - 项目类别:
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