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
- 来源:
- 关键词:AnimalsBRAIN initiativeBasal GangliaBase PairingBehaviorBioinformaticsBiomedical EngineeringBirdsBrainCellsCerebral cortexCerebrumClinicalClustered Regularly Interspaced Short Palindromic RepeatsCodeCognitionCommunitiesComplexCorpus striatum structureDNADataDependovirusDevelopmentEngineeringEnzymesEventFoundationsFunctional disorderGenesGeneticGenomeGenomicsGlutamatesGoalsHealthHumanHuman Cell LineInterneuronsKnowledgeLinkMacacaMammalsMethodsMolecular BiologyMolecular GeneticsMonitorMonkeysMusNervous system structureNeurobiologyNeuronsNeurosciencesNeurosciences ResearchNeurosurgeonNucleotidesOutcomePerceptionPhysiciansPilot ProjectsPrimatesProsencephalonPsyche structureRNAReagentResearchResearch PersonnelResourcesRodentScientistSongbirdsSystemTechnologyTestingThalamic structureTissuesTranslatingTranslationsTransplantationValidationVertebratesViralViral Vectoradenosine deaminasebasebehavioral studybrain cellbrain tissuecell typecombinatorialdata managementdata sharingdesignepigenomicsexperienceexpression vectorflexibilitygamma-Aminobutyric Acidgenetic approachhuman diseasein vivointerestneural circuitneuropsychiatric disordernew technologynovelprogramssensorsingle-cell RNA sequencingtooltranscriptomicsvectorvocal learningzebra finch
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
期刊论文数量(0)
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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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