Role of Stress Granule Protein Aggregation in Axon Regeneration
应激颗粒蛋白聚集在轴突再生中的作用
基本信息
- 批准号:10647839
- 负责人:
- 金额:$ 53.42万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAcuteAddressAdultAffectAttenuatedAutomobile DrivingAxonAxotomyBindingBiologicalCellsCentral Nervous SystemChronicClinicalCommunitiesComplexCytoplasmic GranulesDataFRAP1 geneG3BP1 geneGrowthGrowth Associated Protein 43HourHumanImportinsIn VitroIndividualInjuryKnowledgeLesionLiteratureMessenger RNAMolecularMotorNatural regenerationNerveNerve RegenerationNeuronsNeurosciencesPathway interactionsPeptidesPeripheral NervesPeripheral Nervous SystemPeripheral nerve injuryPermeabilityPhosphorylationPhosphorylation InhibitionPhosphotransferasesPhysiologicalPopulationProtein BiosynthesisProteinsPublishingRNARNA, Messenger, StoredRegenerative capacityRegulationReportingResearchRoleSensorySignal TransductionSolidSpecificitySpinal CordSpinal cord injuryTertiary Protein StructureTestingTherapeuticTimeTissuesTranslatingTranslational ActivationTranslationsViralWorkaxon growthaxon injuryaxon regenerationcalreticulincasein kinaseclinically relevantcohortin vivoinjuredinjury and repairinsightknock-downmRNA Translationnerve injuryneural repairneuromechanismnovel therapeutic interventionoverexpressionpermissivenessprogramsprotein aggregationrecruitreinnervationrepairedresponse to injurystress granuletool
项目摘要
Peripheral nerves spontaneously regenerate but the axon growth rate is abysmally slow, such that
complete functional reinnervation of targets is rarely achieved in humans. Axon regeneration in
the central nervous system is even worse, such that individuals with spinal cord injury (SCI)
almost invariably have permanent lose of sensory and motor functions below the level of the lesion.
There is a pressing need to accelerate axon regeneration in the peripheral nervous system and
increase axon regeneration in the central nervous system. Our research program focuses on axon
intrinsic mechanisms of regeneration. Intra-axonally synthesized proteins support axon growth in
developing neurons. We have shown that PNS neurons retain the capacity to synthesize proteins in
their axons and these proteins support growth of injured axons. Axons of cultured neurons contain
thousands of mRNAs – and several lines of evidence point to complex populations of mRNAs in CNS
axons in vivo and spinal cord axons contain mRNAs and translational machinery when encouraged to
regenerate with permissive substrates. Despite
remarkable advances since the early 2000’s, the molecular mechanisms that determine when and where
a specific mRNA is translated in axons remain largely unknown. This level of regulation is
critical for regulating axon growth capacity. We have shown that mRNAs are stored in PNS axons in
RNA-protein aggregates that contain the stress granule protein G3BP1. G3BP1 protein can drive
stress granule aggregation, and G3BP1 phosphorylation blocks stress granule assembly. Unlike the
classically defined stress granule, axonal G3PB1 protein shows aggregation in uninjured/functioning
PNS axons. These axonal G3BP1 aggregates rapidly increase after axotomy, but decrease to below
basal levels shortly thereafter with a corresponding increase in phosphorylated G3BP1. G3BP1 binds
to mRNAs in axons and attenuates their translation. We have discovered exogenous agents and
endogenous signals that trigger disassembly of axonal G3BP1 aggregates. The exogenous agents
specifically increase axonal protein synthesis and accelerate axon growth rates in vitro and in
vivo. These observations have led us to hypothesize that physiological aggregation of stress
granule proteins in axons attenuates axon growth in the injured PNS and CNS by blocking translation
of an axonal mRNA cohort. We will test this hypothesis with the following specific aims:
Aim 1 – Promotion of axon growth by inhibition of G3BP1 function.
Aim 2 – Endogenous mechanisms for axonal G3BP1 aggregate disassembly.
Aim 3 – Mechanisms driving axon growth upon disassembly of axonal G3BP1 aggregates.
Functional roles for axonal translation have now come to light and we have solid in vivo evidence
that this mechanism can be targeted to accelerate axon growth after acute peripheral nerve injury.
Completion of the proposed research will bring new insight into mechanisms for temporal regulation
of axonal mRNA translation in axon injury & regeneration and uncover new therapeutic strategies for
neural repair.
周围神经自发再生,但轴突生长速率速度较慢,以至于
在人类中,很少实现目标的完全功能性接触。轴突再生
中枢神经系统甚至更糟,因此脊髓损伤的人(SCI)
几乎总是在病变水平以下的感觉和运动功能的永久丧失。
在周围神经系统中加速轴突再生的迫切需要
增加中枢神经系统中的轴突再生。我们的研究计划着重于轴突
再生的内在机制。轴内合成的蛋白支持轴突在
发展神经元。我们已经表明,PNS神经元保留合成蛋白质的能力
它们的轴突和这些蛋白支持受伤的轴突的生长。培养神经元的轴突包含
成千上万的mRNA - 有几条证据表明CNS中mRNA的复杂种群
鼓励体内轴突和脊髓轴突包含mRNA和翻译机械。
用允许的底物再生。尽管
自2000年代初以来的显着进步,确定何时何地的分子机制
特定的mRNA被翻译成轴突,但基本上未知。这种法规是
对调节轴突增长能力至关重要。我们已经证明mRNA存储在PNS轴突中
含有应力颗粒蛋白G3BP1的RNA蛋白聚集体。 G3BP1蛋白可以驱动
应力颗粒聚集,G3BP1磷酸化阻断应力颗粒组件。不像
经典定义的应力颗粒,轴突G3PB1蛋白在未受伤/功能中显示聚集
PNS轴突。这些轴突G3BP1在轴切开术后迅速增加,但降低到低于
此后不久,基本水平随磷酸化的G3BP1的相应增加。 G3BP1结合
向轴突中的mRNA降低了它们的翻译。我们发现了外源性剂和
触发轴突G3BP1聚集体拆卸的内源信号。外源剂
明确增加了轴突蛋白合成和体外和IN加速轴突生长速率
体内。这些观察结果使我们假设压力的身体聚集
轴突中的颗粒蛋白通过阻塞翻译来减弱受伤的PN和CNS的轴突生长
轴突mRNA队列。我们将以以下特定目的检验这一假设:
AIM 1 - 通过抑制G3BP1功能促进轴突生长。
AIM 2 - 轴突G3BP1聚集拆卸的内源机制。
AIM 3 - 在轴突G3BP1聚集体拆卸后推动轴突生长的机制。
轴突翻译的功能作用现已亮起,我们有固体体内证据
急性周围神经损伤后,该机制可以靶向加速轴突生长。
拟议研究的完成将为临时调节的机制带来新的见解
轴突损伤和再生和发现新的治疗策略中的轴突mRNA翻译
神经修复。
项目成果
期刊论文数量(9)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Profiling Locally Translated mRNAs in Regenerating Axons.
分析再生轴突中局部翻译的 mRNA。
- DOI:10.1007/978-1-0716-3012-9_8
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Sahoo,PabitraK;Twiss,JefferyL
- 通讯作者:Twiss,JefferyL
Neurobiology: Resetting the axon's batteries.
神经生物学:重置轴突的电池。
- DOI:10.1016/j.cub.2021.06.014
- 发表时间:2021
- 期刊:
- 影响因子:0
- 作者:Twiss,JefferyL;Kalinski,AshleyL;Sahoo,PabitraK;Costa,IreneDalla;Giger,RomanJ
- 通讯作者:Giger,RomanJ
PTBP1 regulates injury responses and sensory pathways in adult peripheral neurons.
- DOI:10.1126/sciadv.adi0286
- 发表时间:2023-07-28
- 期刊:
- 影响因子:13.6
- 作者:Alber, Stefanie;Di Matteo, Pierluigi;Zdradzinski, Matthew D.;Dalla Costa, Irene;Medzihradszky, Katalin F.;Kawaguchi, Riki;Di Pizio, Agostina;Freund, Philip;Panayotis, Nicolas;Marvaldi, Letizia;Doron-Mandel, Ella;Okladnikov, Nataliya;Rishal, Ida;Nevo, Reinat;Coppola, Giovanni;Lee, Seung Joon;Sahoo, Pabitra K.;Burlingame, Alma L.;Twiss, Jeffery L.;Fainzilber, Mike
- 通讯作者:Fainzilber, Mike
Age-related loss of axonal regeneration is reflected by the level of local translation.
- DOI:10.1016/j.expneurol.2020.113594
- 发表时间:2021-05
- 期刊:
- 影响因子:5.3
- 作者:van Erp S;van Berkel AA;Feenstra EM;Sahoo PK;Wagstaff LJ;Twiss JL;Fawcett JW;Eva R;Ffrench-Constant C
- 通讯作者:Ffrench-Constant C
The glycine arginine-rich domain of the RNA-binding protein nucleolin regulates its subcellular localization.
- DOI:10.15252/embj.2020107158
- 发表时间:2021-10-18
- 期刊:
- 影响因子:0
- 作者:Doron-Mandel E;Koppel I;Abraham O;Rishal I;Smith TP;Buchanan CN;Sahoo PK;Kadlec J;Oses-Prieto JA;Kawaguchi R;Alber S;Zahavi EE;Di Matteo P;Di Pizio A;Song DA;Okladnikov N;Gordon D;Ben-Dor S;Haffner-Krausz R;Coppola G;Burlingame AL;Jungwirth P;Twiss JL;Fainzilber M
- 通讯作者:Fainzilber M
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JEFFERY L TWISS其他文献
JEFFERY L TWISS的其他文献
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{{ truncateString('JEFFERY L TWISS', 18)}}的其他基金
Role of Stress Granule Protein Aggregation in Axon Regeneration
应激颗粒蛋白聚集在轴突再生中的作用
- 批准号:
10265401 - 财政年份:2020
- 资助金额:
$ 53.42万 - 项目类别:
Role of Stress Granule Protein Aggregation in Axon Regeneration
应激颗粒蛋白聚集在轴突再生中的作用
- 批准号:
10406395 - 财政年份:2020
- 资助金额:
$ 53.42万 - 项目类别:
Role of Stress Granule Protein Aggregation in Axon Regeneration
应激颗粒蛋白聚集在轴突再生中的作用
- 批准号:
10447127 - 财政年份:2020
- 资助金额:
$ 53.42万 - 项目类别:
Role of Stress Granule Protein Aggregation in Axon Regeneration
应激颗粒蛋白聚集在轴突再生中的作用
- 批准号:
10030563 - 财政年份:2020
- 资助金额:
$ 53.42万 - 项目类别:
Destabilization of axonal mRNAs by KHSRP complexes during axon regeneration
轴突再生过程中 KHSRP 复合物导致轴突 mRNA 不稳定
- 批准号:
10666545 - 财政年份:2015
- 资助金额:
$ 53.42万 - 项目类别:
Destabilization of axonal mRNAs by KHSRP complexes during axon regeneration
轴突再生过程中 KHSRP 复合物导致轴突 mRNA 不稳定
- 批准号:
10430242 - 财政年份:2015
- 资助金额:
$ 53.42万 - 项目类别:
Destabilization of axonal mRNAs by KHSRP complexes during axon regeneration
轴突再生过程中 KHSRP 复合物导致轴突 mRNA 不稳定
- 批准号:
10306001 - 财政年份:2015
- 资助金额:
$ 53.42万 - 项目类别:
Systems dynamics of intracellular communication (Spatial 2011)
细胞内通讯的系统动力学(Spatial 2011)
- 批准号:
8129400 - 财政年份:2011
- 资助金额:
$ 53.42万 - 项目类别:
KINETICS OF AXONAL PROTEIN SYNTHESIS AND RNA TRANSPORT
轴突蛋白合成和 RNA 运输的动力学
- 批准号:
8363796 - 财政年份:2011
- 资助金额:
$ 53.42万 - 项目类别:
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