Childhood-onset hypomyelinating leukodystrophy and the multi-tRNA synthetase complex
儿童期发病的低髓鞘性脑白质营养不良和多 tRNA 合成酶复合物
基本信息
- 批准号:10582441
- 负责人:
- 金额:$ 62.66万
- 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
- 起止时间:2022-12-15 至 2027-11-30
- 项目状态:未结题
- 来源:
- 关键词:AffectAmino AcidsAmino Acyl-tRNA SynthetasesAnticodonAtaxiaAutomobile DrivingBehavioralBindingCRISPR/Cas technologyCell NucleusCellsCentral Nervous SystemCentral Nervous System DiseasesCerebellar DiseasesCerebrumChildChildhoodClinicalCodeCognitiveComplexCytoplasmDefectDevelopmental Delay DisordersDisparateDistantElementsEtiologyExhibitsFunctional disorderGait abnormalityGenesGenetic CodeGlutamatesGrowthHeterozygoteHuman InbreedingImpaired cognitionIntellectual functioning disabilityKnock-in MouseLamin Type ALettersLife ExpectancyLigaseLigationMediatingMessenger RNAMethylationMicrocephalyMolecularMotorMusMutant Strains MiceMutateMutationMyelinNeural ConductionNeurodegenerative DisordersNeurologicNeurologic DeficitNomenclatureNuclearNuclear ExportOligodendrogliaParentsPathologicPathologic NystagmusPathologyPathway interactionsPeripheral NervesPhenotypePoint MutationPoly(ADP-ribose) PolymerasesPositioning AttributePost-Transcriptional RegulationProlineProtein BiosynthesisProteinsRecombinantsRepressionRoleSiblingsSpecificitySystemTestingTherapeuticTherapeutic InterventionTrans-ActivatorsTranscriptTransfer RNATransfer RNA AminoacylationTranslationsVariantadverse outcomebrain magnetic resonance imagingcell typecurative treatmentsearly adolescenceexome sequencingexperimental studyglutamic acid-tRNAglutamyl-prolyl-tRNA synthetasein vivoin vivo Modelknock-downleukodystrophylymphoblastoid cell linemotor impairmentmouse modelmutantmyelinationnoveloligodendrocyte precursorpreclinical evaluationprecursor cellprenatalprogramsproline-tRNAprotein expressionsingle nucleus RNA-sequencingsmall hairpin RNAspasticitytherapeutic RNAtranscriptomicsvirtual
项目摘要
Project Summary/Abstract
Child-onset hypomyelinating leukodystrophy (HLD) is a genetically heterogeneous group of neurodegenerative
diseases characterized by reduced cerebral myelin formation. Clinical features include cognitive as well as
motor impairment appearing in childhood. There are no curative treatments. Our collaborator, Dr. Grace Yoon,
evaluated two siblings presenting with severe neurological deficit and a shared phenotype consisting of global
developmental delay and intellectual disability, prenatal onset undergrowth and microcephaly, rotatory
nystagmus, ataxia and progressive gait disturbance/spasticity, and hypomyelination on brain MRI. Whole
exome sequencing revealed homozygosity of a c.4444C>A mutation in the EPRS1 gene. The mutation is in
the coding sequence (cds) of the gene causing a Pro-to-Thr point mutation at aa position 1482. The EPRS1
gene encodes the bifunctional, glutamyl-prolyl tRNA synthetase (EPRS1) that resides in the cytoplasmic multi-
tRNA synthetase complex (MSC). The P1482T mutation is located near the C-terminus of the protein in a
region of the Pro synthetase outside the catalytic or anti-codon recognition domains. The specific activity of
recombinant P1482T mutant EPRS1 is indistinguishable from wild-type. In contrast, EPRS1 protein expression
in immortalized lymphoblastoid cell lines (LCL) from affected siblings is about 20% of that in unaffected
controls. EPRS1 mRNA levels are identical in siblings and controls indicating post-transcriptional regulation.
Our preliminary studies show a dual mechanism determining diminished EPRS1 level in affected LCLs,
namely, decreased nuclear export of mutant mRNA, followed by decreased cytoplasmic translation. We show
that decreased EPRS1 expression causes release of other MSC constituents. Remarkably, suppression of
several other MSC components causally implicated in HLD also induce MSC constituent release, suggesting a
common etiology of an entire class of HLDs. We hypothesize that inefficient nuclear export and translation of
c.4444C>A EPRS1 mRNA reduces MSC-bound EPRS1, causing release of MSC constituents and driving the
HLD phenotype. Likewise, defects in genes encoding other MSC constituents share a common pathway and
etiology of HLD. We will test this hypothesis by pursuing these Specific Aims: In Aim 1 we will elucidate
molecular mechanisms underlying reduced expression of EPRS1P1482T variant, focusing on the role of m6A
methylation. Aim 2 determines the HLD-related phenotype of our newly generated, genetically-modified
Eprs1P1482T mice. In Aim 3 we will investigate effect of deficiency of MSC constituents on MSC integrity and
adverse consequences in myelinating oligodendrocytes. A CNS-specific transcriptomic analysis will be done by
single-nucleus RNA-sequencing. Completion of these studies will elucidate a unique mechanism of gene
dysregulation that induces HLD, and will provide a unique mouse model of HLD that will permit detailed in vivo
analysis of the cellular defects in HLD. Importantly, these results suggest the possibility of specific, RNA-based
therapeutic intervention to rescue translation of the variant EPRS1 mRNA and rescue the neurologic defect.
项目摘要/摘要
儿童起病的低髓素性白质营养不良症(HLD)是一组遗传异质性的神经退行性疾病
以脑髓鞘形成减少为特征的疾病。临床特征包括认知能力和
运动障碍出现在儿童时期。目前还没有根治的方法。我们的合作者,Grace Yoon博士,
评估了两个兄弟姐妹,他们都有严重的神经功能缺陷,并有共同的表型,包括
发育迟缓和智力残疾,产前发病发育不足和小头畸形,旋转
眼球震颤,共济失调和进行性步态障碍/痉挛,以及脑部MRI上的髓鞘减少。整体
外显子组测序显示EPRS1基因中的C.4444C>;A突变是纯合的。突变是在
导致AA1482位Pro-to-Thr点突变的基因的编码序列(CDS)。《环境政策与政策》第1期
该基因编码存在于细胞质中的双功能谷氨酰脯氨基tRNA合成酶(EPRS1).
TRNA合成酶复合体(MSC)。P1482T突变位于蛋白的C末端附近
Pro合成酶催化或反密码子识别结构域外的区域。的特定活动
重组P1482T突变体EPRS1与野生型难以区分。相反,EPRS1蛋白的表达
在来自患病同胞的永生化淋巴母细胞系(LCL)中,约为未患病患者的20%
控制。EPRS1的mRNA水平在兄弟姐妹和对照中是相同的,表明转录后调控。
我们的初步研究表明,在受影响的LCLS中,EPRS1水平下降是一种双重机制,
也就是说,突变mRNA的核输出减少,随后细胞质翻译减少。我们展示了
EPRS1表达的降低会导致其他MSC成分的释放。值得注意的是,对
与HLD有因果关系的其他几种MSC成分也可以诱导MSC成分的释放,这表明
一整类HLDS的常见病因。我们假设低效的核出口和翻译
C.44C>;A EPRS1 mRNA减少与MSC结合的EPRS1,导致MSC成分释放,并推动
HLD表型。同样,编码其他间充质干细胞成分的基因缺陷共享共同的途径和
HLD的病因学。我们将通过追求以下具体目标来检验这一假设:在目标1中,我们将阐明
EPRS1P1482T变异体表达降低的分子机制,重点是M6A的作用
甲基化。目标2决定了我们新产生的、转基因的HLD相关表型
Eprs1P1482T小鼠。在目标3中,我们将调查MSC成分缺乏对MSC完整性和
少突胶质细胞髓鞘形成的不良后果。一项针对中枢神经系统的转录分析将由
单核RNA测序。这些研究的完成将阐明一种独特的基因机制
导致肝豆状核变性的调节失调,并将提供一种独特的肝豆状核变性小鼠模型,将允许在体内进行详细的
肝豆状核变性的细胞缺陷分析。重要的是,这些结果表明,特定的、基于RNA的
治疗干预,挽救EPRS1变异基因的翻译,挽救神经功能缺陷。
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 }}
Ranjan Dutta其他文献
Ranjan Dutta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('Ranjan Dutta', 18)}}的其他基金
Molecular correlates of sub-regional thalamic degeneration in multiple sclerosis
多发性硬化症亚区域丘脑变性的分子相关性
- 批准号:
10449474 - 财政年份:2022
- 资助金额:
$ 62.66万 - 项目类别:
Understanding role of circadian disruption in pathogenesis of MS
了解昼夜节律紊乱在多发性硬化症发病机制中的作用
- 批准号:
10442857 - 财政年份:2022
- 资助金额:
$ 62.66万 - 项目类别:
Molecular correlates of sub-regional thalamic degeneration in multiple sclerosis
多发性硬化症亚区域丘脑变性的分子相关性
- 批准号:
10553206 - 财政年份:2022
- 资助金额:
$ 62.66万 - 项目类别:
Understanding role of circadian disruption in pathogenesis of MS
了解昼夜节律紊乱在多发性硬化症发病机制中的作用
- 批准号:
10574570 - 财政年份:2022
- 资助金额:
$ 62.66万 - 项目类别:
MicroRNAs as critical regulators of remyelination in Multiple Sclerosis
MicroRNA 作为多发性硬化症髓鞘再生的关键调节因子
- 批准号:
9272452 - 财政年份:2016
- 资助金额:
$ 62.66万 - 项目类别:
相似海外基金
Double Incorporation of Non-Canonical Amino Acids in an Animal and its Application for Precise and Independent Optical Control of Two Target Genes
动物体内非规范氨基酸的双重掺入及其在两个靶基因精确独立光学控制中的应用
- 批准号:
BB/Y006380/1 - 财政年份:2024
- 资助金额:
$ 62.66万 - 项目类别:
Research Grant
Quantifying L-amino acids in Ryugu to constrain the source of L-amino acids in life on Earth
量化 Ryugu 中的 L-氨基酸以限制地球生命中 L-氨基酸的来源
- 批准号:
24K17112 - 财政年份:2024
- 资助金额:
$ 62.66万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Collaborative Research: RUI: Elucidating Design Rules for non-NRPS Incorporation of Amino Acids on Polyketide Scaffolds
合作研究:RUI:阐明聚酮化合物支架上非 NRPS 氨基酸掺入的设计规则
- 批准号:
2300890 - 财政年份:2023
- 资助金额:
$ 62.66万 - 项目类别:
Continuing Grant
Basic research toward therapeutic strategies for stress-induced chronic pain with non-natural amino acids
非天然氨基酸治疗应激性慢性疼痛策略的基础研究
- 批准号:
23K06918 - 财政年份:2023
- 资助金额:
$ 62.66万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Molecular mechanisms how arrestins that modulate localization of glucose transporters are phosphorylated in response to amino acids
调节葡萄糖转运蛋白定位的抑制蛋白如何响应氨基酸而被磷酸化的分子机制
- 批准号:
23K05758 - 财政年份:2023
- 资助金额:
$ 62.66万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Molecular recognition and enantioselective reaction of amino acids
氨基酸的分子识别和对映选择性反应
- 批准号:
23K04668 - 财政年份:2023
- 资助金额:
$ 62.66万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Design and Synthesis of Fluorescent Amino Acids: Novel Tools for Biological Imaging
荧光氨基酸的设计与合成:生物成像的新工具
- 批准号:
2888395 - 财政年份:2023
- 资助金额:
$ 62.66万 - 项目类别:
Studentship
Structurally engineered N-acyl amino acids for the treatment of NASH
用于治疗 NASH 的结构工程 N-酰基氨基酸
- 批准号:
10761044 - 财政年份:2023
- 资助金额:
$ 62.66万 - 项目类别:
Lifestyle, branched-chain amino acids, and cardiovascular risk factors: a randomized trial
生活方式、支链氨基酸和心血管危险因素:一项随机试验
- 批准号:
10728925 - 财政年份:2023
- 资助金额:
$ 62.66万 - 项目类别:
Single-molecule protein sequencing by barcoding of N-terminal amino acids
通过 N 端氨基酸条形码进行单分子蛋白质测序
- 批准号:
10757309 - 财政年份:2023
- 资助金额:
$ 62.66万 - 项目类别:














{{item.name}}会员




