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Gaining insight into psychiatric disease by engineering piece by piece the human brain in vitro.

Gaining insight into psychiatric disease by engineering piece by piece the human brain in vitro.
通过在体外对人脑进行逐个改造,深入了解精神疾病。
批准号:
10645198
负责人:
Sergiu Pasca
金额:
$65.75万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2015
资助国家:
美国
项目状态:
未结题
起止时间:
2015-08-01 至 2025-05-31
关键词:
16p11.23-DimensionalAccelerationAcetylcholineAffectAnatomyAwardBrainBrain DiseasesBrain StemBrain regionCRISPR/Cas technologyCalciumCell CommunicationCell LineCellsCentral Nervous SystemCerebral cortexCommunicationCoupledCouplingDefectDevelopmentDiseaseDisease modelDopamineElectrophysiology (science)EngineeringFunctional disorderGene ExpressionGenesGeneticGlutamatesGoalsGrowth FactorHigh Pressure Liquid ChromatographyHumanHuman BiologyHybridsImageIn VitroInterneuronsInvestigationLaboratoriesLentivirusMeasurementMental disordersMethodsModelingMolecularNamesNational Institute of Mental HealthNervous SystemNeurobiologyNeurodevelopmental DisorderNeuromodulatorNeuronsNeurosciencesOpsinOrganOrganoidsPathogenesisPatientsPatternPharmaceutical PreparationsPharmacologyPhenotypePhysiologicalPlayPluripotent Stem CellsPositioning AttributePreparationProcessProliferatingPropertyProsencephalonRodent ModelRoleSelective Serotonin Reuptake InhibitorSerotonergic SystemSerotoninSignal TransductionSliceSynapsesSyndromeSystemTechnologyTestingTherapeuticViralWorkatypical antipsychoticaxon guidancebrain tissuecohortdirected differentiationexperimental studyhuman modelhuman pluripotent stem cellimmunocytochemistryinsightmigrationneuralneural networkneurodevelopmentneuronal excitabilityneuropsychiatric disorderneuropsychiatryneuroregulationnext generationnovelnovel strategiesoptogeneticspatch clampprogenitorprogramsrabies viral tracingraphe nucleireceptorsocial deficitsstem cell biologystem cell modelthree dimensional structuretranscriptomics

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英文摘要
ABSTRACT A critical challenge in understanding the intricate programs underlying development, assembly, function, and dysfunction of the human nervous system is the lack of direct access to intact, functioning human brain tissue for detailed investigation by imaging, recording, and stimulation. My laboratory has been developing methods for directed differentiation of region-specific brain organoids and we have shown that these can combined two by two to study cell-cell interactions and circuit formation in preparations called brain assembloids. However, current in vitro brain models derived from stem cells do not capture neuromodulatory input, which restrict broader applications in neuroscience and modeling of disease. Here, we propose to develop a human 3D cellular platform that includes neuromodulatory projections. More specifically, we will derive from pluripotent stem cells regionalized brain organoids resembling the nucleus raphe in the brainstem and containing serotonergic neurons, and subsequently assemble them with cortical organoids. Using state-of-the-art live imaging, transcriptomics, pharmacology, viral tracing and electrophysiological methods, we plan to study serotonergic input into the cerebral cortex and use this platform to investigate defects in neuronal cross-talk in a severe genetic form of neurodevelopmental disease.
期刊论文(11)
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会议论文
DOI: 10.1038/s41596-018-0032-7
发表时间: 2018-09
期刊: Nature protocols
影响因子: 14.8
作者: [Sloan SA, Andersen J, Pașca AM, Birey F, Pașca SP]
通讯作者: Pașca SP
DOI: 10.1016/j.neuron.2017.07.035
发表时间: 2017-08-16
期刊: Neuron
影响因子: 16.2
作者: [Sloan SA, Darmanis S, Huber N, Khan TA, Birey F, Caneda C, Reimer R, Quake SR, Barres BA, Paşca SP]
通讯作者: Paşca SP
DOI: 10.1016/j.cell.2020.11.017
发表时间: 2020-12-23
期刊: Cell
影响因子: 64.5
作者: [Andersen J, Revah O, Miura Y, Thom N, Amin ND, Kelley KW, Singh M, Chen X, Thete MV, Walczak EM, Vogel H, Fan HC, Paşca SP]
通讯作者: Paşca SP
DOI: 10.1038/s41587-020-00763-w
发表时间: 2020-12
期刊: NATURE BIOTECHNOLOGY
影响因子: 46.9
作者: [Miura, Yuki, Li, Min-Yin, Birey, Fikri, Ikeda, Kazuya, Revah, Omer, Thete, Mayuri Vijay, Park, Jin-Young, Puno, Alyssa, Lee, Samuel H., Porteus, Matthew H., Pasca, Sergiu P.]
通讯作者: Pasca, Sergiu P.
7
    Role of L-type Calcium Channels in Human Interneuron Migration and Integration
    • 批准号:
      9427931
    • 项目类别:
    • 资助金额:
      $54.92万
    • 财政年份:
      2018
    • 负责人:
      Sergiu Pasca
    • 依托单位:
    Role of L-type Calcium Channels in Human Interneuron Migration and Integration
    • 批准号:
      9762226
    • 项目类别:
    • 资助金额:
      $58.67万
    • 财政年份:
      2018
    • 负责人:
      Sergiu Pasca
    • 依托单位:
    Role of L-type Calcium Channels in Human Interneuron Migration and Integration
    • 批准号:
      9918982
    • 项目类别:
    • 资助金额:
      $57.47万
    • 财政年份:
      2018
    • 负责人:
      Sergiu Pasca
    • 依托单位:
    Role of L-type Calcium Channels in Human Interneuron Migration and Integration
    • 批准号:
      10391481
    • 项目类别:
    • 资助金额:
      $52.62万
    • 财政年份:
      2018
    • 负责人:
      Sergiu Pasca
    • 依托单位:
    海外基金