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

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.
核苷酸重复扩增突变引起进行性和致死性神经退行性疾病

项目成果

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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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