Molecular Origins of Neurodegeneration through Force Detangling of Toxic RNA
通过强制解开有毒 RNA 导致神经退行性变的分子起源
基本信息
- 批准号:10667873
- 负责人:
- 金额:$ 24.17万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-03-15 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAmyotrophic Lateral SclerosisBase PairingBinding ProteinsBiologicalBiological AssayBrainCAG repeatCationsCell AggregationCell DeathCell SeparationCellsCellular biologyChemicalsComplexDeteriorationDevelopmentDiseaseFutureGelGenesGoalsGrowthHumanHuntington DiseaseHuntington geneIn VitroInheritedKineticsKnowledgeLateralLinkLiquid substanceMeasuresMessenger RNAMethodsMicrofluidicsMolecularMutationNerve DegenerationNeurodegenerative DisordersNeurofibrillary TanglesNeurogliaNeuronsNucleotidesPathogenesisPathogenicityPathologicPhysical condensationProcessProteinsRNARNA ProbesRNA-Binding ProteinsRNA-Protein InteractionReactionResearchRiskSpectrum AnalysisSpinocerebellar AtaxiasStressStretchingStructureTestingTimeToxic effectTrinucleotide RepeatsTriplet Multiple BirthVariantWorkX-Ray Crystallographybaseconfocal imagingflexibilityfluidityfluorescence imagingfluorophoregenome wide association studyimaging capabilitieslaser tweezermechanical propertiesmethod developmentmolecular imagingmolecular pathologymouse modelmutantneurotoxicitynew therapeutic targetnovel strategiesoptic trapoptic tweezeroptical trapsphysical propertypolyglutamineprotein complexsingle moleculesmall moleculesmall molecule inhibitortool
项目摘要
Nucleotide repeat expansion mutations cause progressive and lethal neurodegenerative
diseases such as Huntington’s Disease (HD) and amyotrophic lateral schlerosis (ALS). The
molecular reasons for the pathological effects of these mutations remain elusive. Most research
has focused on the toxic effects of the mutant proteins. The expanded repeat RNA, however,
has more recently been shown to be toxic to neurons and to contribute to disease. In
Huntington’s Disease, RNA containing 40 or more CAG repeats is known to associate with
itself, condensing into gel-like assemblies or aggregates. Nevertheless, the stability and
dynamics of the RNA interactions inside these condensates and aggregates are little known. It
is also not known what features of the RNA, if any, correlate with disease propensity. This lack
of progress is in part owing to the difficulty of studying interactions that are repetitive,
heterogeneous, and changeable. This project will develop a new single molecule tool to study
the structures and mechanical properties of abnormal CAG sequences in huntingtin mRNA.
Sensitive optical traps will be used to manipulate and unfold single RNA molecules. Integrated
real-time confocal fluorescence imaging of fluorophore-tagged RNA with microfluidics control of
the reaction components will track the build-up or dissolution of the RNA and protein complexes.
The first aim will determine the structure and stability of normal and expanded RNA and
compare them with the localization, aggregation, and toxicity of huntingtin RNA and protein in
cells. The second aim is to develop a real-time single molecule confocal assay to study the
mechanism of aggregation. The third aim is to develop a method for pulling on natural huntingtin
RNA complexes or aggregates isolated from cells, to understand how these aberrant structures
contribute to pathogenesis. Although this single force-spectroscopy method for studying RNA
aggregation is untried, the results have the potential to provide new information on the
molecular pathology of nucleotide repeat diseases. In the future, our single molecule tools can
be applied to many different RNA repeats and used to test small molecule inhibitors. The long-
term goal of this research is to identify a physical signature of huntingtin mRNA interactions that
predict neurotoxicity and that can be targeted by new therapies.
核苷酸重复序列扩增突变导致进行性和致死性神经退行性变
亨廷顿病(HD)和肌萎缩侧索硬化症(ALS)等疾病。这个
这些突变的病理效应的分子原因仍然难以捉摸。大多数研究
已经将重点放在了突变蛋白质的毒性效应上。然而,扩展的重复RNA,
最近被证明对神经元有毒性,并导致疾病。在……里面
亨廷顿病,含有40个或更多CAG重复的RNA与已知的
本身,凝聚成凝胶状的组件或聚集体。尽管如此,稳定和
这些凝聚体和聚集体中的RNA相互作用的动力学鲜为人知。它
也不知道RNA的哪些特征(如果有的话)与疾病倾向相关。这种缺失
进步的部分原因是很难研究重复的相互作用,
异质的,多变的。该项目将开发一种新的单分子工具来研究
亨廷顿蛋白基因中异常CAG序列的结构和力学性质。
灵敏的光学陷阱将被用来操纵和展开单个RNA分子。集成
微流控实时共聚焦荧光成像研究荧光团标记RNA
反应成分将跟踪RNA和蛋白质复合体的建立或溶解。
第一个目标将确定正常和扩展的RNA的结构和稳定性
将它们与亨廷顿蛋白和亨廷顿蛋白的定位、聚集和毒性在
细胞。第二个目标是建立一种实时单分子共聚焦分析方法来研究
聚集机制。第三个目标是开发一种拉动自然狩猎的方法
从细胞中分离的RNA复合体或聚集体,以了解这些异常结构是如何
在发病机制中起作用。尽管这种研究RNA的单力谱学方法
如果未尝试聚合,则结果有可能提供有关
核苷酸重复疾病的分子病理学。在未来,我们的单分子工具可以
被应用于许多不同的RNA重复序列,并用于测试小分子抑制剂。长的-
这项研究的术语目标是确定Huntingtin mRNA相互作用的物理特征
预测神经毒性,这可以成为新疗法的靶点。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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专利数量(0)
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Christian Kaiser其他文献
Christian Kaiser的其他文献
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{{ truncateString('Christian Kaiser', 18)}}的其他基金
Folding and Chaperone Interactions of Multi-domain Proteins
多结构域蛋白质的折叠和分子伴侣相互作用
- 批准号:
10446687 - 财政年份:2017
- 资助金额:
$ 24.17万 - 项目类别:
Single-molecule studies of Sec-dependent protein translocation
Sec 依赖性蛋白质易位的单分子研究
- 批准号:
9374906 - 财政年份:2017
- 资助金额:
$ 24.17万 - 项目类别:
Folding and chaperone interactions of multi-domain proteins
多结构域蛋白质的折叠和分子伴侣相互作用
- 批准号:
9217889 - 财政年份:2017
- 资助金额:
$ 24.17万 - 项目类别:
Folding and Chaperone Interactions of Multi-domain Proteins
多结构域蛋白质的折叠和分子伴侣相互作用
- 批准号:
10662086 - 财政年份:2017
- 资助金额:
$ 24.17万 - 项目类别:
Single molecule analysis of nascent protein folding
新生蛋白质折叠的单分子分析
- 批准号:
7570874 - 财政年份:2008
- 资助金额:
$ 24.17万 - 项目类别:
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