RNA targeting tools with novel specific RNA-guided RNA-targeting CRISPR effectors

具有新型特异性 RNA 引导 RNA 靶向 CRISPR 效应器的 RNA 靶向工具

基本信息

  • 批准号:
    10457098
  • 负责人:
  • 金额:
    $ 36.3万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-01 至 2022-08-31
  • 项目状态:
    已结题

项目摘要

Project Summary Despite extraordinary advances in genome engineering, tools for precise and efficient transcriptome engineering are lacking. While we and others have characterized novel programmable RNA targeting CRISPR systems, such as Cas13, and developed tools from these systems, use of these tools have been limited in cellular systems due to a non-promiscuous cleavage activity known as collateral activity, and the main application for Cas13 has been rapid and sensitive nucleic acid testing using the collateral activity for reporter signal generation. While Cas13 has been shown to have specific RNA cleavage activity in some cell types, other cell types have had significant collateral cleavage of cellular RNAs, leading to toxicity in cell models. An ideal RNA targeting tool for mammalian applications would lack collateral activity and only cleave the targeted substrate. The proposed work will address these needs by combining computational discovery, biochemical characterization, and enzyme engineering to find new RNA targeting CRISPR nucleases, adapt these enzymes for mammalian use, and develop specific RNA targeting tools for transcriptome engineering and transcriptome-wide screening. The discovery and characterization of these new CRISPR proteins will both build upon our deep history of CRISPR enzyme work, as well as draw from new, high-throughput approaches to mine biological diversity. We will search for families with RNase domains enriched near CRISPR arrays and characterize these enzymes. Preliminary characterization of one RNase containing family, containing Cas7-like RAMP RNase domains, here termed Cas7-11, shows RNA cleavage of specific targets using short guide RNAs without observable collateral activity. This Cas7-11 effector belongs to type III-E systems and is the first characterized single-protein effector in Class 1 systems. We characterize the mechanism of Cas7-11, show the residues that make it catalytically inactive for RNA binding applications, and engineer Cas7-11 for RNA knockdown and editing in mammalian cells. Using the specific Cas7-11 tool, we propose developing a single technology that is capable of RNA knockdown, RNA editing, or RNA splicing based on the crRNA, allowing multiple RNA perturbations to be accomplished in a single genome wide RNA targeting screen and allowing for cell circuits to be efficiently interrogated. The multiple technologies resulting from these discoveries and engineering efforts will overcome the limitations of existing transcriptome engineering approaches and serve as a valuable resource for broader biomedical research. Moreover, this gene exploration and engineering framework will serve as a model for discovering diverse bacterial genes, evaluating biochemical activity across a range of assays, and converting these findings into high impact biotechnologies. The developed technologies will accelerate the pace of biomedical research and enable greater exploration of basic biological processes and disease mechanisms.
项目总结

项目成果

期刊论文数量(0)
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Omar O Abudayyeh其他文献

Omar O Abudayyeh的其他文献

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{{ truncateString('Omar O Abudayyeh', 18)}}的其他基金

Developing programmable RNA writing tools with the novel RNA-guided RNA-targeting CRISPR effector Cas7-11
使用新型 RNA 引导的 RNA 靶向 CRISPR 效应器 Cas7-11 开发可编程 RNA 写入工具
  • 批准号:
    10736989
  • 财政年份:
    2023
  • 资助金额:
    $ 36.3万
  • 项目类别:
Discovery and manipulation of transcription factors to restore long term stem cell repopulation in aged bone-marrow
发现和操纵转录因子以恢复衰老骨髓中的长期干细胞增殖
  • 批准号:
    10334958
  • 财政年份:
    2022
  • 资助金额:
    $ 36.3万
  • 项目类别:
Discovery and manipulation of transcription factors to restore long term stem cell repopulation in aged bone-marrow
发现和操纵转录因子以恢复衰老骨髓中的长期干细胞增殖
  • 批准号:
    10676080
  • 财政年份:
    2022
  • 资助金额:
    $ 36.3万
  • 项目类别:
Programmable gene integration and cell engineering with CRISPR-directed integrases
使用 CRISPR 引导的整合酶进行可编程基因整合和细胞工程
  • 批准号:
    10672995
  • 财政年份:
    2021
  • 资助金额:
    $ 36.3万
  • 项目类别:
Programmable gene integration and cell engineering with CRISPR-directed integrases
使用 CRISPR 引导的整合酶进行可编程基因整合和细胞工程
  • 批准号:
    10279165
  • 财政年份:
    2021
  • 资助金额:
    $ 36.3万
  • 项目类别:
Programmable gene integration and cell engineering with CRISPR-directed integrases
使用 CRISPR 引导的整合酶进行可编程基因整合和细胞工程
  • 批准号:
    10491366
  • 财政年份:
    2021
  • 资助金额:
    $ 36.3万
  • 项目类别:

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