Suppression of disease causingnonsense mutations by targeted mRNA pseudouridylation

通过靶向 mRNA 假尿苷化抑制引起无义突变的疾病

基本信息

  • 批准号:
    9805188
  • 负责人:
  • 金额:
    $ 16.75万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-07-01 至 2021-06-30
  • 项目状态:
    已结题

项目摘要

In this exploratory grant application, we propose to fully develop a novel approach, namely, targeted RNA pseudouridylation, to suppress nonsense mutations in genes that cause diseases (e.g., nonsense mutations in the CFTR gene that cause Cystic Fibrosis, and nonsense mutations in p53 gene that cause various types of cancer). This project, if successful, will constitute a giant step toward our ultimate goal of developing novel therapeutic treatment for a number of genetic disorders and certain types of cancer caused by nonsense mutations. We propose to carry out this project under two specific aims. Aim 1. To improve the efficiency of RNA-guided pseudouridylation in human cells. We will improve the efficiency of targeted mRNA pseudouridylation by identifying a better modifying enzyme (specifically, a better box H/ACA guide RNA). We will focus on the three elements within the guide RNA that have been identified (by our lab and other labs) to be important for directing pseudouridylation, and construct a perfect box H/ACA guide RNA. We will also engineer the guide RNA by adding a nucleoplasmic localization signal, thus targeting the guide RNA (and RNP) to the nucleoplasm where mRNA is synthesized and matures. Finally, we will increase box H/ACA RNA expression level, thus raising its concentration in the nucleoplasm of human cells. In doing so, we believe we will be able to create a super guide RNA that can efficiently direct site-specific mRNA pseudouridylation. Aim 2. To directly target the PTC within a disease gene in human disease cell lines. Using an designer box H/ACA RNA (especially when the improved super box H/ACA RNA identified in Aim 1 is available), we will directly target the premature termination codon (PTC, resulting from nonsense mutations) within the CFTR mRNA in a CF cell line and within the p53 mRNA in a human cancer cell line. The efficiency of guide RNA transfection and its expression level in transfected cells will be measured. Site-specific pseudouridylation at the PTC of mRNAs will also be quantified. Furthermore, nonsense suppression, including the suppression of NMD (nonsense-mediated mRNA decay) and PTC read-through, will be monitored. In short, this proposal presents a potential novel approach to treat many genetic diseases and certain types of cancer associated with nonsense mutations.
在这个探索性的拨款申请中,我们建议充分开发一种新颖的方法,即目标

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 }}

YI-TAO YU其他文献

YI-TAO YU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('YI-TAO YU', 18)}}的其他基金

Pseudouridine-mediated branch site recognition/selection during pre-mRNA splicing
前 mRNA 剪接过程中假尿苷介导的分支位点识别/选择
  • 批准号:
    10383755
  • 财政年份:
    2020
  • 资助金额:
    $ 16.75万
  • 项目类别:
Pseudouridine-mediated branch site recognition/selection during pre-mRNA splicing
前 mRNA 剪接过程中假尿苷介导的分支位点识别/选择
  • 批准号:
    10612829
  • 财政年份:
    2020
  • 资助金额:
    $ 16.75万
  • 项目类别:
Pseudouridine-mediated branch site recognition/selection during pre-mRNA splicing
前 mRNA 剪接过程中假尿苷介导的分支位点识别/选择
  • 批准号:
    10231213
  • 财政年份:
    2020
  • 资助金额:
    $ 16.75万
  • 项目类别:
Pseudouridine-mediated branch site recognition/selection during pre-mRNA splicing
前 mRNA 剪接过程中假尿苷介导的分支位点识别/选择
  • 批准号:
    10026485
  • 财政年份:
    2020
  • 资助金额:
    $ 16.75万
  • 项目类别:
Expanding the genetic code by targeted pseudouridylation
通过靶向假尿苷化扩展遗传密码
  • 批准号:
    8550118
  • 财政年份:
    2012
  • 资助金额:
    $ 16.75万
  • 项目类别:
Expanding the genetic code by targeted pseudouridylation
通过靶向假尿苷化扩展遗传密码
  • 批准号:
    8914641
  • 财政年份:
    2012
  • 资助金额:
    $ 16.75万
  • 项目类别:
Expanding the genetic code by targeted pseudouridylation
通过靶向假尿苷化扩展遗传密码
  • 批准号:
    8419298
  • 财政年份:
    2012
  • 资助金额:
    $ 16.75万
  • 项目类别:
Regulation of telomerase activity and aging by 2'-O-methylation in telomerase RNA
端粒酶RNA中2-O-甲基化对端粒酶活性和衰老的调节
  • 批准号:
    8516934
  • 财政年份:
    2012
  • 资助金额:
    $ 16.75万
  • 项目类别:
Expanding the genetic code by targeted pseudouridylation
通过靶向假尿苷化扩展遗传密码
  • 批准号:
    8720024
  • 财政年份:
    2012
  • 资助金额:
    $ 16.75万
  • 项目类别:
Regulation of telomerase activity and aging by 2'-O-methylation in telomerase RNA
端粒酶RNA中2-O-甲基化对端粒酶活性和衰老的调节
  • 批准号:
    8242209
  • 财政年份:
    2012
  • 资助金额:
    $ 16.75万
  • 项目类别:

相似海外基金

Determining how 2'-O-methylations in the eukaryotic anticodon loop region of tRNA are formed and how they affect translation
确定 tRNA 真核反密码子环区域中 2-O-甲基化的形成方式以及它们如何影响翻译
  • 批准号:
    10438971
  • 财政年份:
    2018
  • 资助金额:
    $ 16.75万
  • 项目类别:
Codon-anticodon coevolution in invertebrate mitochondrial genomes
无脊椎动物线粒体基因组中的密码子-反密码子协同进化
  • 批准号:
    370096-2008
  • 财政年份:
    2008
  • 资助金额:
    $ 16.75万
  • 项目类别:
    University Undergraduate Student Research Awards
Elucidation of reaction mechanism for post-transcriptional modification at tRNA anticodon region
阐明 tRNA 反密码子区域转录后修饰的反应机制
  • 批准号:
    20687007
  • 财政年份:
    2008
  • 资助金额:
    $ 16.75万
  • 项目类别:
    Grant-in-Aid for Young Scientists (A)
Role of the Elongator complex in tRNA anticodon modification and intracellular stress signaling (B02)
Elongator 复合物在 tRNA 反密码子修饰和细胞内应激信号传导中的作用 (B02)
  • 批准号:
    5447893
  • 财政年份:
    2005
  • 资助金额:
    $ 16.75万
  • 项目类别:
    Collaborative Research Centres
THE ANTICODON AND ITS INFLUENCE ON TRNA IDENTITY
反密码子及其对 TRNA 身份的影响
  • 批准号:
    3045064
  • 财政年份:
    1990
  • 资助金额:
    $ 16.75万
  • 项目类别:
THE ANTICODON AND ITS INFLUENCE ON TRNA IDENTITY
反密码子及其对 TRNA 身份的影响
  • 批准号:
    3045063
  • 财政年份:
    1990
  • 资助金额:
    $ 16.75万
  • 项目类别:
Study on the biosynthesis of the modified uridine derivatives at the first position of the anticodon of tRNA
tRNA反密码子第一位修饰尿苷衍生物的生物合成研究
  • 批准号:
    61571061
  • 财政年份:
    1986
  • 资助金额:
    $ 16.75万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (C)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了