The COPA vesicle protein and pathogenesis of spinal muscular atrophy
COPA囊泡蛋白与脊髓性肌萎缩症发病机制
基本信息
- 批准号:10612848
- 负责人:
- 金额:$ 38.22万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-08-15 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:3&apos Untranslated RegionsAffectAlzheimer&aposs DiseaseAmyotrophic Lateral SclerosisApplications GrantsAxonAxonal TransportBindingBinding ProteinsBiochemicalBiologicalCRISPR/Cas technologyCarrier ProteinsCellsCo-ImmunoprecipitationsCoat Protein Complex IComplexCoupledDataDefectDependenceDevelopmentDiseaseEndoplasmic ReticulumEtiologyFormaldehydeFunctional disorderG-Protein-Coupled ReceptorsGenesGeneticGolgi ApparatusGrantHigh-Throughput RNA SequencingImmunoprecipitationIn VitroInfant MortalityIntracellular TransportInvestigationLearningLinkLipidsLongevityMaintenanceMessenger RNAMicroRNAsModelingMolecularMorphologyMotorMotor NeuronsMovementMusMuscleMuscle WeaknessMutationMyopathyNerveNerve DegenerationNeuritesNeurodegenerative DisordersNeuromuscular JunctionNeuronal DysfunctionNeuronsNucleic AcidsOutcomePathogenesisPathologicPathway interactionsPeptide Signal SequencesProcessPropertyProteinsProteomicsPublishingRNARNA-Binding ProteinsReportingRoleSMN protein (spinal muscular atrophy)SeriesSpinal Muscular AtrophySystemTechniquesTest ResultTestingTissuesTransgenic MiceTransgenic OrganismsTransmembrane TransportVesicleWestern Blottingcopingcrosslinkembryonic stem cellexosomeexperimental studyextracellular vesiclesin vivoinsightmotor neuron functionmouse modelmutantneuronal cell bodynoveloverexpressionpharmacologicreceptor bindingtrafficking
项目摘要
ABSTRACT
The pathogenesis of motor neuron and muscle dysfunction in spinal muscular atrophy (SMA), a leading genetic
cause of infant mortality, is still unresolved. SMA results from low levels of the Survival Motor Neuron SMN
protein. The rationale underlying these experiments is our discovery that the SMN protein binds to and moves
in neurons together with the CopA protein, the largest constituent of the heptameric COPI coatomer complex.
The objective of this proposal is to determine the molecular mechanisms by which reduced SMN interaction
with COPI complex and loss of COPI activities leads to neurodegeneration. Golgi-derived COPI vesicles are
necessary for post-translational processing and transport of proteins and other cargoes between Golgi
apparatus and endoplasmic reticulum and secretory pathway. Golgi alterations have been observed in SMA,
amyotrophic lateral sclerosis, Alzheimer’s disease, and other neurodegenerative disorders. Our data
demonstrate that pathologically low levels of SMN alter the morphology and functionality of the Golgi
apparatus. The overall premise of this proposal is that the COPI complex is necessary for processing and
trafficking of cargoes essential for normal motor neuron maintenance. We have also shown that specific
mRNAs are found in association with COPI. One class of cargo emphasized in this grant is mRNA selected for
axonal transport. We propose genetic, biochemical, proteomic and transgenic approaches to define the
properties and activities of the COPI complex and its interactions with SMN and other potential binding
partners. We will create murine models to investigate the role of COPI in the neuron and perform correlative in
vivo studies of axonogenesis, RNA trafficking and pathologic biological outcomes. Because SMN physically
interacts with factors linked to other neurodegenerative diseases, thereby implicating commonality of causality,
these experiments should result in new insights into the aberrant processes occurring in these disorders.
Moreover, pharmacologic induction of the COPI pathway may represent a novel objective for treatment of SMA
and other neurodegenerative diseases.
摘要
脊髓性肌萎缩症(SMA)是一种主要的遗传性疾病,
婴儿死亡的原因仍然没有得到解决。SMA由低水平的运动神经元生存SMN引起
蛋白这些实验的基本原理是我们发现SMN蛋白结合并移动
在神经元中与CopA蛋白一起,CopA蛋白是七聚体COPI外被体复合物的最大成分。
本提案的目的是确定减少SMN相互作用的分子机制
与COPI复合物和COPI活性的丧失导致神经变性。高尔基体衍生的COPI囊泡是
蛋白质和其他货物在高尔基体之间的翻译后加工和运输所必需的
内质网和分泌途径。在SMA中观察到高尔基体改变,
肌萎缩侧索硬化症、阿尔茨海默病和其他神经退行性疾病。我们的数据
证明病理性低水平的SMN改变了高尔基体的形态和功能
设备.本提案的总体前提是,COPI复合体对于处理和
运输对正常运动神经元维持必不可少的货物。我们还表明,
发现mRNA与COPI相关。在这项资助中强调的一类货物是mRNA,
轴突运输我们提出了遗传学、生物化学、蛋白质组学和转基因的方法来定义
COPI复合物的性质和活性及其与SMN和其他潜在结合的相互作用
伙伴我们将建立小鼠模型来研究COPI在神经元中的作用,并进行相关的研究。
轴突发生、RNA运输和病理生物学结果的体内研究。因为SMN在物理上
与其他神经退行性疾病相关因素相互作用,从而暗示因果关系的共性,
这些实验应该导致对这些疾病中发生的异常过程的新的认识。
此外,COPI通路的药物诱导可能代表SMA治疗的新目标
和其他神经退行性疾病。
项目成果
期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Abnormal Golgi morphology and decreased COPI function in cells with low levels of SMN.
- DOI:10.1016/j.brainres.2018.11.005
- 发表时间:2019-03-01
- 期刊:
- 影响因子:2.9
- 作者:Custer SK;Foster JN;Astroski JW;Androphy EJ
- 通讯作者:Androphy EJ
Interaction between alpha-COP and SMN ameliorates disease phenotype in a mouse model of spinal muscular atrophy.
α-COP 和 SMN 之间的相互作用可改善脊髓性肌萎缩小鼠模型的疾病表型。
- DOI:10.1016/j.bbrc.2019.04.176
- 发表时间:2019
- 期刊:
- 影响因子:3.1
- 作者:Custer,SaraK;Astroski,JacobW;Li,HongXia;Androphy,ElliotJ
- 通讯作者:Androphy,ElliotJ
Mutations in the COPI coatomer subunit α-COP induce release of Aβ-42 and amyloid precursor protein intracellular domain and increase tau oligomerization and release.
- DOI:10.1016/j.neurobiolaging.2021.01.003
- 发表时间:2021-05
- 期刊:
- 影响因子:4.2
- 作者:Astroski JW;Akporyoe LK;Androphy EJ;Custer SK
- 通讯作者:Custer SK
Differential regulation of the SMN2 gene by individual HDAC proteins.
- DOI:10.1016/j.bbrc.2011.09.011
- 发表时间:2011-10-14
- 期刊:
- 影响因子:3.1
- 作者:Evans MC;Cherry JJ;Androphy EJ
- 通讯作者:Androphy EJ
Autophagy dysregulation in cell culture and animals models of spinal muscular atrophy.
- DOI:10.1016/j.mcn.2014.06.006
- 发表时间:2014-07
- 期刊:
- 影响因子:0
- 作者:Custer SK;Androphy EJ
- 通讯作者:Androphy EJ
{{
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 }}
ELLIOT J. ANDROPHY其他文献
ELLIOT J. ANDROPHY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('ELLIOT J. ANDROPHY', 18)}}的其他基金
Small Molecule E6 Inhibitors to Treat Oropharyngeal Cancers Caused by HPV Infections
小分子 E6 抑制剂治疗 HPV 感染引起的口咽癌
- 批准号:
10484043 - 财政年份:2022
- 资助金额:
$ 38.22万 - 项目类别:
Small Molecule E6 Inhibitors to Treat Dysplasia Caused by HPV Infections
小分子 E6 抑制剂治疗 HPV 感染引起的发育异常
- 批准号:
10390563 - 财政年份:2022
- 资助金额:
$ 38.22万 - 项目类别:
Development of a mouse model to test HPV Antiviral compounds
开发小鼠模型来测试 HPV 抗病毒化合物
- 批准号:
10582890 - 财政年份:2022
- 资助金额:
$ 38.22万 - 项目类别:
Small-Molecule Covalent E6 Antagonists for Treatment of HPV Infection
小分子共价 E6 拮抗剂治疗 HPV 感染
- 批准号:
10220227 - 财政年份:2021
- 资助金额:
$ 38.22万 - 项目类别:
Small-Molecule Covalent E6 Antagonists for Treatment of HPV Infection
小分子共价 E6 拮抗剂治疗 HPV 感染
- 批准号:
10397131 - 财政年份:2021
- 资助金额:
$ 38.22万 - 项目类别:
Small-Molecule Covalent E6 Antagonists for Treatment of HPV Infection
小分子共价 E6 拮抗剂治疗 HPV 感染
- 批准号:
10610388 - 财政年份:2021
- 资助金额:
$ 38.22万 - 项目类别:
Optimization of a novel series of thiazolopyridines for the treatment of SMA
用于治疗 SMA 的新型噻唑并吡啶系列的优化
- 批准号:
8892548 - 财政年份:2015
- 资助金额:
$ 38.22万 - 项目类别:
Toward drug treatment of spinal muscular atrophy: Mechanism of action
脊髓性肌萎缩症的药物治疗:作用机制
- 批准号:
8823350 - 财政年份:2014
- 资助金额:
$ 38.22万 - 项目类别:
The COPA vesicle protein and pathogenesis of spinal muscular atrophy
COPA囊泡蛋白与脊髓性肌萎缩症发病机制
- 批准号:
8866202 - 财政年份:2013
- 资助金额:
$ 38.22万 - 项目类别:
The Indiana Cutaneous Biological Research Training Program
印第安纳州皮肤生物学研究培训计划
- 批准号:
8827676 - 财政年份:2013
- 资助金额:
$ 38.22万 - 项目类别:
相似海外基金
Impact of alternative polyadenylation of 3'-untranslated regions in the PI3K/AKT cascade on microRNA
PI3K/AKT 级联中 3-非翻译区的替代多聚腺苷酸化对 microRNA 的影响
- 批准号:
573541-2022 - 财政年份:2022
- 资助金额:
$ 38.22万 - 项目类别:
University Undergraduate Student Research Awards
How do untranslated regions of cannabinoid receptor type 1 mRNA determine receptor subcellular localisation and function?
1 型大麻素受体 mRNA 的非翻译区如何决定受体亚细胞定位和功能?
- 批准号:
2744317 - 财政年份:2022
- 资助金额:
$ 38.22万 - 项目类别:
Studentship
MICA:Synthetic untranslated regions for direct delivery of therapeutic mRNAs
MICA:用于直接递送治疗性 mRNA 的合成非翻译区
- 批准号:
MR/V010948/1 - 财政年份:2021
- 资助金额:
$ 38.22万 - 项目类别:
Research Grant
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
- 批准号:
10019570 - 财政年份:2019
- 资助金额:
$ 38.22万 - 项目类别:
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
- 批准号:
10223370 - 财政年份:2019
- 资助金额:
$ 38.22万 - 项目类别:
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
- 批准号:
10455108 - 财政年份:2019
- 资助金额:
$ 38.22万 - 项目类别:
Synergistic microRNA-binding sites, and 3' untranslated regions: a dialogue of silence
协同的 microRNA 结合位点和 3 非翻译区:沉默的对话
- 批准号:
255762 - 财政年份:2012
- 资助金额:
$ 38.22万 - 项目类别:
Operating Grants
Analysis of long untranslated regions in Nipah virus genome
尼帕病毒基因组长非翻译区分析
- 批准号:
20790351 - 财政年份:2008
- 资助金额:
$ 38.22万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
Search for mRNA elements involved in the compatibility between 5' untranslated regions and coding regions in chloroplast translation
寻找参与叶绿体翻译中 5 非翻译区和编码区之间兼容性的 mRNA 元件
- 批准号:
19370021 - 财政年份:2007
- 资助金额:
$ 38.22万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Post-transcriptional Regulation of PPAR-g Expression by 5'-Untranslated Regions
5-非翻译区对 PPAR-g 表达的转录后调控
- 批准号:
7131841 - 财政年份:2006
- 资助金额:
$ 38.22万 - 项目类别: