Exploring a new arm of the integrated stress response and its connection to neurodegeneration
探索综合应激反应的新分支及其与神经退行性变的联系
基本信息
- 批准号:10303995
- 负责人:
- 金额:$ 41.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2022-12-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAmino AcidsAmino Acyl-tRNA SynthetasesAminoacylationArchitectureBiologyCell NucleusCell SurvivalCellsCellular Stress ResponseCharacteristicsCharcot-Marie-Tooth DiseaseClinicalCollaborationsCytoplasmDeformityDiseaseDistalDrosophila genusEnzymesEtiologyEukaryotic CellEukaryotic Initiation FactorsEventFamily memberFutureGene FamilyGenesGeneticGrantHereditary Motor and Sensory NeuropathiesHeterogeneityIndividualInheritedLimb structureLinkMammalian CellMediatingMetabolic stressModelingMolecularMolecular ProfilingMuscleMutationNamesNerve DegenerationNeurodegenerative DisordersNeuropathyNuclearNuclear TranslocationPathogenesisPathway interactionsPatientsPeripheral NervesPeripheral Nervous System DiseasesPhosphorylationPrevalenceProgram DevelopmentPropertyProtein BiosynthesisReactionRecoveryRoleSensorySignal TransductionStressSymptomsSystemTestingTherapeuticTimeTimeLineTranscriptional ActivationTransfer RNA AminoacylationTranslationsUnited StatesYangactivating transcription factorarmbiological adaptation to stresscurative treatmentsdisease-causing mutationdisorder subtypedrug developmentenvironmental stressorflygain of functiongene repressionin vivoin vivo Modelin vivo evaluationinsightmotor impairmentneurotoxicrepairedskeletaltherapeutic developmenttreatment strategyupstream kinasewasting
项目摘要
Charcot-Marie-Tooth disease (CMT), also known as hereditary motor and sensory neuropathy (HMSN), is the
most common form of inherited peripheral neuropathy, with an estimated prevalence of 1 in 2500 individuals,
equating to approximately 125,000 people in the United States. CMT specifically targets peripheral nerves and
is characterized by weakness and wasting of the distal limb muscles leading to progressive motor impairment,
sensory loss, and skeletal deformities. No curative therapy is available for CMT patients. The largest gene family
implicated in CMT encodes aminoacyl-tRNA synthetases (aaRSs), which are essential enzymes catalyzing a
key reaction in protein biosynthesis, namely, the charging of transfer RNAs (tRNAs) with their cognate amino
acids. So far, the causality between dominant aaRS mutations and CMT has been firmly established in 5 family
members (YARS1, GARS1, AARS1, HARS1, and WARS1). Despite some heterogeneities, clinical presentations
of CMT patients with aaRSs mutations are highly similar, implying shared disease mechanisms. Notably, we and
others have demonstrated that CMT-causing mutations do not necessarily affect the tRNA aminoacylation
function of the enzymes. Instead, a potentially common neurotoxic gain of function is thought to be responsible
for the neuropathy, however, its molecular basis remains largely elusive. In this proposal, we aim to test a
unifying central hypothesis that dysregulation of a new arm of the Integrated Stress Response (ISR), specifically
regulated by aaRSs in the nucleus, contributes to the etiology of CMT. We propose that this new arm of ISR is
related to - but distinct from - the classical eIF2a phosphorylation mediated ISR pathway. Because of the different
timeline of this stress response, we name it the Late Integrates Stress Response (LISR). We speculate that
CMT-linked aaRSs might all be LISR-regulating aaRSs and that dysregulation of the cellular stress response
system by CMT mutations results in neurodegeneration. The project will be carried out in close collaboration
between Yang and Jordanova labs to explore the shared molecular mechanism by which dominant mutations in
5 different aaRSs cause CMT. Our exploration will direct future in-depth mechanistic studies and drug
development programs for this severe disease. Moreover, this project will advance our understanding of basic
biology through establishing a new stress response pathway specially regulated by aaRSs.
腓骨肌萎缩症(CMT),也称为遗传性运动和感觉神经病(HMSN),是一种遗传性运动和感觉神经病。
最常见的遗传性周围神经病,估计患病率为1/2500,
相当于美国约125,000人。CMT专门针对外周神经,
其特征在于远端肢体肌肉的虚弱和消耗,导致进行性运动障碍,
感觉丧失和骨骼畸形CMT患者无治愈性治疗。最大的基因家族
参与CMT编码氨酰-tRNA合成酶(aaRS),这是催化
蛋白质生物合成中的关键反应,即转运RNA(tRNA)与其同源氨基的电荷
acids.迄今为止,已在5个家系中证实了显性阿尔斯突变与CMT之间的因果关系
成员(YARS 1、GARS 1、AARS 1、HARS 1和WARS 1)。尽管存在一些异质性,但临床表现
的CMT患者与aaRSs突变高度相似,这意味着共同的疾病机制。值得注意的是,我们和
其他人已经证明引起CMT的突变不一定影响tRNA的氨酰化,
酶的功能。相反,一种潜在的常见神经毒性功能的获得被认为是负责的
然而,对于神经病,其分子基础在很大程度上仍然是难以捉摸的。在本提案中,我们的目标是测试
统一的中心假设,即综合应激反应(ISR)的一个新分支的失调,特别是
由细胞核中的aaRSs调节,有助于CMT的病因学。我们建议这个新的ISR部门
与经典eIF 2a磷酸化介导的ISR途径相关但不同。因为不同的
这种应激反应的时间轴,我们称之为晚期整合应激反应(LISR)。我们推测
CMT连锁的aaRSs可能都是LISR调节的aaRSs,细胞应激反应的失调
系统因CMT突变而导致神经退行性变。该项目将在密切合作下进行。
Yang和Jordanova实验室之间的合作,以探索显性突变的共同分子机制,
5种不同的aaRS导致CMT。我们的探索将指导未来深入的机制研究和药物治疗
针对这种严重疾病的发展计划。此外,这个项目将促进我们对基本的理解,
通过建立aaRSs特异性调控的新的应激反应途径,
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
An Adapted GeneSwitch Toolkit for Comparable Cellular and Animal Models: A Proof of Concept in Modeling Charcot-Marie-Tooth Neuropathy.
- DOI:10.3390/ijms242216138
- 发表时间:2023-11-09
- 期刊:
- 影响因子:5.6
- 作者:
- 通讯作者:
Tyrosyl-tRNA synthetase has a noncanonical function in actin bundling.
酪蛋白-TRNA合成酶在肌动蛋白捆绑中具有非规范功能。
- DOI:10.1038/s41467-023-35908-3
- 发表时间:2023-03-08
- 期刊:
- 影响因子:16.6
- 作者:Ermanoska, Biljana;Asselbergh, Bob;Morant, Laura;Petrovic-Erfurth, Maria-Luise;Hosseinibarkooie, Seyyedmohsen;Leitao-Goncalves, Ricardo;Almeida-Souza, Leonardo;Bervoets, Sven;Sun, Litao;Lee, LaTasha;Atkinson, Derek;Khanghahi, Akram;Tournev, Ivaylo;Callaerts, Patrick;Verstreken, Patrik;Yang, Xiang-Lei;Wirth, Brunhilde;Rodal, Avital A.;Timmerman, Vincent;Goode, Bruce L.;Godenschwege, Tanja A.;Jordanova, Albena
- 通讯作者:Jordanova, Albena
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Xiang-Lei Yang其他文献
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{{ truncateString('Xiang-Lei Yang', 18)}}的其他基金
Develop pan-specific antibody against mutant glycyl-tRNA synthetase for treating CMT2D
开发抗突变甘氨酰-tRNA合成酶的泛特异性抗体来治疗 CMT2D
- 批准号:
10544795 - 财政年份:2021
- 资助金额:
$ 41.06万 - 项目类别:
Link extracellular function of tRNA synthetase with pathological mechanism of disease
将tRNA合成酶的细胞外功能与疾病的病理机制联系起来
- 批准号:
10630282 - 财政年份:2021
- 资助金额:
$ 41.06万 - 项目类别:
Link extracellular function of tRNA synthetase with pathological mechanism of disease
将tRNA合成酶的细胞外功能与疾病的病理机制联系起来
- 批准号:
10405421 - 财政年份:2021
- 资助金额:
$ 41.06万 - 项目类别:
Develop pan-specific antibody against mutant glycyl-tRNA synthetase for treating CMT2D
开发抗突变甘氨酰-tRNA合成酶的泛特异性抗体来治疗 CMT2D
- 批准号:
10541284 - 财政年份:2021
- 资助金额:
$ 41.06万 - 项目类别:
2015 Translation Machinery in Health & Disease Gordon Research Conference
2015年健康翻译机
- 批准号:
8831351 - 财政年份:2015
- 资助金额:
$ 41.06万 - 项目类别:
Extra-translational roles of aminoacyl tRNA synthetases in connection to disease
氨酰 tRNA 合成酶与疾病相关的翻译外作用
- 批准号:
8326643 - 财政年份:2010
- 资助金额:
$ 41.06万 - 项目类别:
Extra-translational roles of aminoacyl tRNA synthetases in connection to disease
氨酰 tRNA 合成酶与疾病相关的翻译外作用
- 批准号:
8536318 - 财政年份:2010
- 资助金额:
$ 41.06万 - 项目类别:
Extra-translational roles of aminoacyl tRNA synthetases in connection to disease
氨酰 tRNA 合成酶与疾病相关的翻译外作用
- 批准号:
9177065 - 财政年份:2010
- 资助金额:
$ 41.06万 - 项目类别:
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