RNA-programmable cell type targeting and manipulation across vertebrate nervous systems

跨脊椎动物神经系统的 RNA 可编程细胞类型靶向和操作

基本信息

  • 批准号:
    10350096
  • 负责人:
  • 金额:
    $ 58.63万
  • 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:
    2021-09-13 至 2024-09-12
  • 项目状态:
    已结题

项目摘要

Systematic experimental access to diverse neuronal cell types is a prerequisite to deciphering brain circuit organization, function, and dysfunction. Thus fundamental progress in neuroscience urgently needs cell type access technologies that are specific, comprehensive, easy to use, affordable, scalable, and general across animal species. Most if not all current genetic approaches to cell type targeting are based on genome and DNA engineering, which has inherent limitations in achieving the desired tool features. We have developed a paradigm-shifting technology for cell type targeting and manipulation based on RNA engineering. This technology builds upon the universal RNA sensing and editing system within metazoan cells, centered around the enzyme adenosine deaminase acting on RNA (ADAR). We term this method CellREADR: Cell access through RNA sensing by Endogenous ADAR. CellREADR can be deployed as a single RNA molecule that detects specific cellular RNAs through Watson-Crick base pairing and switches on the translation of markers, sensors, and effectors through a single base editing event; these RNA molecules can be delivered to animals via viral expression vectors. As such, CellREADR is highly specific and comprehensive, fast, cheap, easy to use, scalable, and in principle should apply to all animals. Importantly, CellREADR is inherently programmable, with unprecedented versatility for combinatorial and multiplexed targeting and editing of cell types in complex tissues. In this proposal, we will apply CellREADR to target and validate a large set of neuron types of the broadly defined cerebral cortex and basal ganglia in several mammalian and avian species. Our proposal is grounded on the evolutionary conservation as well as divergence of these forebrain cell types, which may underlie conserved and divergent circuit function and behavior across species. We have assembled an interdisciplinary team of investigators with expertise in molecular genetics, systems neuroscience, human and clinical neuroscience, bioengineering, and computation genomics. First, we will further optimize the CellREADR method and develop a comprehensive set of AAV tools for targeting and manipulating all major transcriptomic types of glutamatergic (GLU) and GABAergic neurons of the mouse cerebral cortex. Second, we will extend CellREADR to target and validate a large set of GLU and GABA neuron types in human ex vivo cortical tissues, macaque monkey cerebral cortex, and zebra finch cortex and basal ganglia. Third, we will establish a central CellREADR Portal for computational design of CellREADR reagents across vertebrate species and dissemination of technology and resource throughout the neuroscience community. By using cell-specific RNA profiles as the basis for genetic access and manipulation, CellREADR cell-editing technology is poised to transform the scale and rate of discovery in neuroscience and across biomedical fields. Impacts on the BRAIN Initiative will be immediate and far-reaching by translating the massive progress in transcriptomic cell types to understanding brain circuit function and dysfunction.
对不同类型的神经细胞进行系统的实验是破解脑回路的先决条件

项目成果

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Z JOSH HUANG其他文献

Z JOSH HUANG的其他文献

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{{ truncateString('Z JOSH HUANG', 18)}}的其他基金

RNA-programmable cell-type targeting, editing, and therapy
RNA 可编程细胞类型靶向、编辑和治疗
  • 批准号:
    10655620
  • 财政年份:
    2021
  • 资助金额:
    $ 58.63万
  • 项目类别:
RNA-programmable cell-type targeting, editing, and therapy
RNA 可编程细胞类型靶向、编辑和治疗
  • 批准号:
    10483215
  • 财政年份:
    2021
  • 资助金额:
    $ 58.63万
  • 项目类别:
Discovering the molecular genetic principles of cell type organization through neurobiology-guided computational analysis of single cell multi-omics data sets
通过神经生物学引导的单细胞多组学数据集计算分析发现细胞类型组织的分子遗传学原理
  • 批准号:
    10189902
  • 财政年份:
    2021
  • 资助金额:
    $ 58.63万
  • 项目类别:
RNA-programmable cell-type targeting, editing, and therapy
RNA 可编程细胞类型靶向、编辑和治疗
  • 批准号:
    10260304
  • 财政年份:
    2021
  • 资助金额:
    $ 58.63万
  • 项目类别:
Transcriptome-based systematic discovery of GABAergic neurons in the neocortex
基于转录组的新皮质 GABA 能神经元的系统发现
  • 批准号:
    9977809
  • 财政年份:
    2016
  • 资助金额:
    $ 58.63万
  • 项目类别:
Transcriptome-based systematic discovery of GABAergic neurons in the neocortex
基于转录组的新皮质 GABA 能神经元的系统发现
  • 批准号:
    9320717
  • 财政年份:
    2016
  • 资助金额:
    $ 58.63万
  • 项目类别:
Transcriptome-based systematic discovery of GABAergic neurons in the neocortex
基于转录组的新皮质 GABA 能神经元的系统发现
  • 批准号:
    9754666
  • 财政年份:
    2016
  • 资助金额:
    $ 58.63万
  • 项目类别:
Neurolucida BrainMaker Imaging System
Neurolucida BrainMaker 成像系统
  • 批准号:
    9075950
  • 财政年份:
    2016
  • 资助金额:
    $ 58.63万
  • 项目类别:
Transcriptome-based systematic discovery of GABAergic neurons in the neocortex
基于转录组的新皮质 GABA 能神经元的系统发现
  • 批准号:
    9083947
  • 财政年份:
    2016
  • 资助金额:
    $ 58.63万
  • 项目类别:
Transcriptome-based systematic discovery of GABAergic neurons in the neocortex
基于转录组的新皮质 GABA 能神经元的系统发现
  • 批准号:
    10319407
  • 财政年份:
    2016
  • 资助金额:
    $ 58.63万
  • 项目类别:

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BRAIN Initiative:分层事件描述符 (HED):表征神经行为数据事件的系统
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  • 财政年份:
    2022
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  • 资助金额:
    $ 58.63万
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