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.
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
中文摘要
摘要
理解开发、组装、
功能,而人体神经系统的功能障碍是缺乏完整的直接进入,
通过成像、记录和刺激对功能正常的人脑组织进行详细研究。
我的实验室一直在开发针对特定区域大脑的定向分化方法,
我们已经证明,这些细胞可以两两结合起来研究细胞间的相互作用,
和回路形成的过程中。然而,目前的体外脑
来自干细胞的模型不能捕获神经调节输入,这限制了更广泛的应用
在神经科学和疾病建模中的应用。在这里,我们建议开发一个人类3D
包括神经调节投射的细胞平台。更具体地说,我们将得到
从多能干细胞区域化的脑类器官类似于中缝核,
脑干和含有多巴胺能神经元,随后将它们与皮质
类器官使用最先进的实时成像,转录组学,药理学,病毒追踪和
电生理学方法,我们计划研究进入大脑皮层的肾上腺素能输入,并使用
这个平台,以调查缺陷的神经元串扰在一个严重的遗传形式,
神经发育疾病
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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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.
Roadmap for developing biologically inspired therapeutics for genetic brain disorders.
开发遗传性脑部疾病的生物启发疗法的路线图。
DOI:
10.1016/j.molmed.2023.07.005
发表时间:
2023
期刊:
Trends in molecular medicine
影响因子:
13.6
作者:
[Imaizumi,Kent, Paşca,SergiuP]
通讯作者:
Paşca,SergiuP
共 7 条
Role of L-type Calcium Channels in Human Interneuron Migration and Integration
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批准号:9427931
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项目类别:
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资助金额:$54.92万
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财政年份:2018
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负责人:Sergiu Pasca
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依托单位:
Role of L-type Calcium Channels in Human Interneuron Migration and Integration
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批准号:9762226
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资助金额:$58.67万
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Role of L-type Calcium Channels in Human Interneuron Migration and Integration
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财政年份:2018
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资助金额:$79.59万
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财政年份:2017
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依托单位:
Cross modal integration of molecular and physiological networks in ASD (2/2)
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批准号:10225520
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资助金额:$80.19万
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依托单位:
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Gaining insight into psychiatric disease by engineering piece by piece the human brain in vitro.
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批准号:10222534
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资助金额:$62.01万
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财政年份:2015
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Gaining insight into psychiatric disease by engineering piece by piece the human brain in vitro.
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批准号:10418740
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项目类别:
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资助金额:$59.67万
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财政年份:2015
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负责人:Sergiu Pasca
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依托单位:
Gaining insight into psychiatric disease by engineering piece by piece the human brain in vitro.
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批准号:8957296
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项目类别:
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资助金额:$48.93万
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财政年份:2015
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负责人:Sergiu Pasca
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依托单位:
Gaining insight into psychiatric disease by engineering piece by piece the human brain in vitro.
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批准号:9267533
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项目类别:
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资助金额:$49.17万
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财政年份:2015
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负责人:Sergiu Pasca
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依托单位:
海外基金