A Massive Library of AAVs to Target Transcriptionally-Defined Primate Cell Types
针对转录定义的灵长类细胞类型的庞大 AAV 库
基本信息
- 批准号:9804256
- 负责人:
- 金额:$ 228.7万
- 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:2019-09-01 至 2022-06-30
- 项目状态:已结题
- 来源:
- 关键词:AdultAnatomyBehaviorBehavioralBrainBrain regionBreedingCapsidCellsClinicalCodeCognitionCognitiveComplexConsensusCorpus striatum structureDNAData SetDatabasesDecision MakingDependovirusDevelopmentDimensionsDiseaseDopamine ReceptorEngineeringEnhancersEquipment and supply inventoriesEvolutionExpression ProfilingFoundationsGene DeliveryGene ExpressionGene Expression ProfileGene Transfer TechniquesGenesGeneticGenetic TranscriptionGenomicsGoalsHumanIndividualInvestigationInvestigational TherapiesLearningLibrariesMacacaMacaca mulattaMapsMediatingMental disordersMethodsMidbrain structureModelingModificationMonitorMonkeysMoodsMotor CortexMusMutateNeurologicNeuronsNeurosciencesOpsinOutcomePhotophobiaPhotosensitivityPhysiologicalPrefrontal CortexPrimatesPropertyRegulatory ElementRetinaRetinal DegenerationRetinal Ganglion CellsRetinal gene therapyRewardsRoleSpecificityStructureSystemThalamic structureTransgenesTropismTyrosine 3-MonooxygenaseUpdateValidationVariantViral VectorVisionadeno-associated viral vectorbasebrain cellcell typecostdopaminergic neuronexperimental studyfunctional restorationgene therapy clinical trialhigh throughput screeninghuman diseaseinnovationminimally invasivemultidisciplinarynervous system disorderneural circuitnonhuman primateoptogeneticspromoterreference genomerelating to nervous systemsingle-cell RNA sequencingsynthetic biologytherapeutic genetherapeutic transgenetooltranscriptometransgene expressionvalidation studiesvectorvisual processing
项目摘要
Here we will identify nonhuman primate (NHP) neuron types and build an extensive toolbox of vectors for circuit-
based neuroscience studies. NHPs share substantial neuroanatomical, genetic, and behavioral homology with
humans, and therefore they are indispensable for investigating the neural circuit basis of cognition and devising
therapies to treat neurological and psychiatric disorders. Despite the importance of NHPs, we lack the tools to
analyze and manipulate complex circuits in the primate brain. This lack severely limits the use of genetically-
coded neuroscience tools to examine circuit specific functions and hinders development of targeted gene
therapeutics. Current methods for achieving transgenesis in small model species, such as the creation of
genetically modified strains, are prohibitively expensive in NHP and not applicable to human disease. AAVs are
the leading alternative to germline modification and selective breeding. AAVs infect adult neurons, confer stable
transgene expression, and have proven safe in gene therapy clinical trials. AAVs do not have natural cell-types
specific properties, but when altered or combined with cell type specific regulatory sequences
(enhancers/promoters) they have been able to achieve cell type-specific transgenesis. This has made possible,
for example, our previous optogenetic investigation of midbrain dopamine neurons for learning and decision
making. However, before AAV-mediated gene delivery can be generalized to circuits across the brain and for
multiple behavioral functions, we must create currently lacking vectors and promoters that permit efficient and
specific gene delivery to all required cell types. Here, we will combine single-cell RNA-Seq (scRNA-Seq) with
high-throughput screening of engineered adeno-associated viruses (AAVs) to create a complete toolbox of viral
vectors and promoters enabling minimally invasive monitoring and manipulation of neurons in NHP brain. We
have devised a transdisciplinary approach to classify individual neurons according to their gene expression
profile and simultaneously screen for adeno-associated virus (AAV) vectors (capsids and regulatory sequences)
capable of specific and efficient transgene delivery to classified neurons. First, we will synthesize massive
libraries of mutated AAV vectors and synthetic promoters, in which each variant is paired with a unique DNA
barcode. We will then scRNA-Seq to capture the transcriptome for each cell and quantify the AAV and promoter-
specific barcodes in every cell’s expression profile. Preliminary experiments in Rhesus monkeys have fully
validated and demonstrated the promise of this innovative approach. The outcomes of our Specific Aims will
include (1) an inventory of cell types in the retina, prefrontal cortex, primary motor cortex, and striatum, (2) cell
type-specific AAVs and promoters targeting all defined cell types, (3) AAVs with broad tropisms, (4) a publicly
available dataset of transcription profiles for millions of NHP brain cells, (5) an updated and comprehensive
Rhesus macaque reference genome, and (6) anatomical, physiological, and functional validation of cell type-
specific circuits tools and their function in the NHP brain.
在这里,我们将识别非人类灵长类动物(NHP)神经元类型,并建立一个广泛的工具箱向量电路-
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)
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William Richard Stauffer其他文献
William Richard Stauffer的其他文献
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{{ truncateString('William Richard Stauffer', 18)}}的其他基金
Cognitive and reward signals for choices under ambiguity
模糊选择的认知和奖励信号
- 批准号:
10344279 - 财政年份:2022
- 资助金额:
$ 228.7万 - 项目类别:
Cognitive and reward signals for choices under ambiguity
模糊选择的认知和奖励信号
- 批准号:
10570887 - 财政年份:2022
- 资助金额:
$ 228.7万 - 项目类别:
Request for a Brainsight Turnkey Neuro-Navigation System For NHP Research
请求用于 NHP 研究的 Brainsight 交钥匙神经导航系统
- 批准号:
10282578 - 财政年份:2021
- 资助金额:
$ 228.7万 - 项目类别:
A Massive Library of AAVs to Target Transcriptionally-Defined Primate Cell Types
针对转录定义的灵长类细胞类型的庞大 AAV 库
- 批准号:
10612511 - 财政年份:2019
- 资助金额:
$ 228.7万 - 项目类别:
A Massive Library of AAVs to Target Transcriptionally-Defined Primate Cell Types
针对转录定义的灵长类细胞类型的庞大 AAV 库
- 批准号:
10188645 - 财政年份:2019
- 资助金额:
$ 228.7万 - 项目类别:
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