Dynamics of Translation
Dynamics of Translation
批准号:
10617792
负责人:
JOSEPH D PUGLISI
金额:
$76.7万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-06-01 至 2027-05-31
关键词:
AreaBindingBinding ProteinsBiochemicalBiochemistryBiophysicsCodeComplexCryoelectron MicroscopyDiseaseEventFundingGene ExpressionGeneticGrantHealthHumanKineticsMessenger RNAMethodsModificationMolecular ConformationNonsense CodonNonsense-Mediated DecayNucleotidesOrganismPathway interactionsProcessQuality ControlRNAReagentRecyclingRegulationResearchRibosomesRoleStructureTerminator CodonTimeTranslation InitiationTranslationsYeastsgenetic regulatory proteinmethod developmentprotein foldingsingle moleculestructural biology
中文摘要
项目概要(30行)
翻译是中心法则的终点,也是时空调控的起点,
基因表达。生物化学、生物物理学和结构学方法已经概述了
翻译的步骤,提供了一个菜单的关键因素,结构的核糖体和复合物,
以及引发、延伸和终止/再循环的基本步骤的动力学。
然而,关键步骤如起始、延伸和终止的机制,
它们是如何被RNA结构、修饰或调节蛋白调节的仍不清楚。
一个关键的挑战是翻译是高度动态的,涉及构象和组成
变化贯穿和遵循异质机制途径。在以往供资期间
我们将在这个MIRA合并的赠款支持期间,我们已经开发了单一的-
分子方法和试剂,观察翻译在真实的时间。我们将这些联合收割机
动态方法与cryoEM结构,以获得时间和详细的机械视图,
过程我们建议的研究重点是关键领域的翻译控制:如何启动是
在高等生物中实现-这里是一个小的(40 S)核糖体亚基被
与mRNA结合并识别启动子-将在酵母和人类中确定,
我们将探讨mRNA结构,蛋白质结合和修饰的核苷酸如何改变
过程我们将研究mRNA的5'端和3'端之间的长距离RNA相互作用是如何发生的。
可能对基础翻译起始及其控制至关重要。在延伸中,我们将继续
探索重新编码事件和共翻译蛋白质折叠,并开发观察方法
真核生物中的翻译延伸。我们将探讨核糖体的作用
停止/暂停并最终分流到核糖体质量控制途径中。最后我们将
了解正确的终止密码子被识别和核糖体再循环的途径
并确定正确与过早终止密码子在无意义中的区别
介导的衰变途径。我们的研究利用了数十年的试剂和方法
发展,和一个奇妙的合作者小组,探索翻译控制,及其
与人类健康和疾病的核心联系。
英文摘要
PROJECT SUMMARY (30 lines)
Translation is the endpoint of the central dogma and point of temporal and spatial regulation in
gene expression. Biochemical, biophysical and structural methods have outlined the general
steps of translation, providing a menu of key factors, structures of ribosomes and complexes,
and kinetics for the essential steps of initiation, elongation and termination/recycling.
Nonetheless, the mechanisms of key steps such as initiation, elongation and termination, and
how they are regulated by RNA structures, modification or regulatory proteins remains unclear.
A key challenge is that translation is highly dynamic, involving conformational and compositional
changes throughout and following heterogeneous mechanistic pathways. During prior funding
periods supported by the grants that we will merge in this MIRA, we have developed single-
molecule approaches and reagents that observe translation in real time. We combine these
dynamic methods with cryoEM structures to gain a temporal and detailed mechanistic view of
the process. Our proposed research focuses on key areas translational control: how initiation is
achieved in higher organisms—here the pathway by which a small (40S) ribosomal subunit is
bound to a mRNA and recognizes a start—will be determined in both yeast and humans, and
we will explore how mRNA structure, protein binding and modified nucleotides change the
process. We will investigate how long-range RNA interaction between 5’ and 3’ ends of mRNAs
may be critical for basal translation initiation and its control. In elongation, we will continue to
explore recoding events and co-translational protein folding and develop methods to watch
translation elongation in eukaryotic organisms. We will explore the role of ribosomal
stalling/pausing and eventual shunting into ribosomal quality control pathways. Finally, we will
understand the pathways by which correct stop codons are recognized and ribosomes recycled
and determine how correct vs premature stop codons are distinguished in the nonsense
mediated decay pathway. Our research leverages decades of reagent and methods
development, and a wonderful group of collaborators to explore translational control, and its
central linkage to human health and disease.
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会议论文
Dynamics of Translation
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批准号:10406800
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项目类别:
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资助金额:$75.95万
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财政年份:2022
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负责人:JOSEPH D PUGLISI
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依托单位:
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负责人:JOSEPH D PUGLISI
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依托单位:
CHEETAH Center for the Structural Biology of HIV Infection, Restriction, and Viral Dynamics
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批准号:10508315
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资助金额:$37.36万
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财政年份:2022
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负责人:JOSEPH D PUGLISI
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依托单位:
Dynamic pathways of eukaryotic translation initiation
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批准号:9327001
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资助金额:$46.19万
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财政年份:2016
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负责人:JOSEPH D PUGLISI
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依托单位:
Dynamics of eukaryotic translation initiation and its control
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批准号:9974210
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项目类别:
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资助金额:$51.95万
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财政年份:2016
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负责人:JOSEPH D PUGLISI
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依托单位:
Modulation of internal ribosome entry by ribosomal protein RPS25
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批准号:9412429
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项目类别:
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资助金额:$58.03万
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财政年份:2014
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负责人:JOSEPH D PUGLISI
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依托单位:
Modulation of internal ribosome entry by ribosomal protein RPS25
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批准号:8697776
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项目类别:
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资助金额:$59.37万
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财政年份:2014
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负责人:JOSEPH D PUGLISI
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依托单位:
Modulation of internal ribosome entry by ribosomal protein RPS25
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批准号:8995180
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项目类别:
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资助金额:$57.77万
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财政年份:2014
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负责人:JOSEPH D PUGLISI
-
依托单位:
Single molecule translational profiling
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批准号:8539806
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项目类别:
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资助金额:$70.03万
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财政年份:2011
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负责人:JOSEPH D PUGLISI
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依托单位:
Single molecule translational profiling
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批准号:8727064
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项目类别:
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资助金额:$72.2万
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财政年份:2011
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负责人:JOSEPH D PUGLISI
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依托单位:
Single molecule translational profiling
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批准号:8338860
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项目类别:
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资助金额:$72.2万
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财政年份:2011
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负责人:JOSEPH D PUGLISI
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依托单位:
Single molecule translational profiling
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批准号:8181683
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项目类别:
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资助金额:$147.2万
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财政年份:2011
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负责人:JOSEPH D PUGLISI
-
依托单位:
Single molecule translational profiling
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批准号:8913990
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项目类别:
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资助金额:$72.2万
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财政年份:2011
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负责人:JOSEPH D PUGLISI
-
依托单位:
A Stanford - SJSU Postdoctoral Training Program to Enhance URM Teaching
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批准号:8131108
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项目类别:
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资助金额:$74.24万
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财政年份:2010
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负责人:JOSEPH D PUGLISI
-
依托单位:
A Stanford - SJSU Postdoctoral Training Program to Enhance URM Teaching
-
批准号:7939074
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项目类别:
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资助金额:$30.01万
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财政年份:2010
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负责人:JOSEPH D PUGLISI
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依托单位:
NMR instrumentation: Stanford core facility 800 MHz console
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批准号:7790418
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项目类别:
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资助金额:$44.61万
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财政年份:2010
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负责人:JOSEPH D PUGLISI
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依托单位:
A Stanford - SJSU Postdoctoral Training Program to Enhance URM Teaching
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批准号:8320213
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项目类别:
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资助金额:$106.51万
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财政年份:2010
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负责人:JOSEPH D PUGLISI
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依托单位:
A Stanford - SJSU Postdoctoral Training Program to Enhance URM Teaching
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批准号:8532928
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项目类别:
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资助金额:$75.54万
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财政年份:2010
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负责人:JOSEPH D PUGLISI
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依托单位:
Eukaryotic Translational Initiation and its Regulation
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批准号:7925560
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项目类别:
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资助金额:$29.72万
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财政年份:2007
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负责人:JOSEPH D PUGLISI
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依托单位:
Eukaryotic Translational Initiation and its Regulation
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批准号:7493754
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项目类别:
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资助金额:$30.02万
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财政年份:2007
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负责人:JOSEPH D PUGLISI
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依托单位:
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