Generation and characterization of MGE-derived GABAergic neurons from human pluripotent stem cells
人多能干细胞 MGE 衍生的 GABA 能神经元的生成和表征
基本信息
- 批准号:9902548
- 负责人:
- 金额:$ 21.19万
- 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:2019-04-01 至 2021-01-31
- 项目状态:已结题
- 来源:
- 关键词:AffectBasic ScienceBindingBiochemicalBiological ModelsBipolar DisorderBone Morphogenetic ProteinsBrainCell modelCellsCharacteristicsClinical ResearchComplementComplement Factor BComplexCuesDataData SetDevelopmentDiseaseDisease modelEctopic ExpressionElectrophysiology (science)ElementsEnhancersEpilepsyEquilibriumFoundationsFunctional disorderFutureGangliaGene Expression ProfilingGene MutationGenerationsGenesGeneticGenetic TranscriptionGoalsHeterogeneityHigh PrevalenceHomeoboxHumanImmunofluorescence ImmunologicIn VitroIndividualInterneuronsInvestigationKnowledgeLaboratoriesLightMedialMental disordersMethodologyMethodsMissionModelingMolecularMorphologyMusMutationNational Institute of Mental HealthNeuronsNeuropsychologyParvalbuminsPatternPhysiologicalPlayPopulationPreventionProcessPropertyProsencephalonProtocols documentationRecoveryRoleSHH geneSchizophreniaSomatostatinSpecific qualifier valueSpecificitySynapsesTestingTetracyclinesTo specifyTrans-ActivatorsTransforming Growth FactorsTransplantationWNT Signaling PathwayWorkautism spectrum disorderbasebipolar patientsbrain tissuecell typedisorder riskexperimental studygenetic risk factorgenetic signaturehuman modelhuman pluripotent stem cellhuman stem cellsinduced pluripotent stem cellinterdisciplinary approachmolecular markermolecular phenotypenerve stem cellnestin proteinnovelnovel strategiesnovel therapeuticsprogenitorresponsesingle-cell RNA sequencingsmoothened signaling pathwaystem cell technologystem cellssuccesstooltranscription factortranscriptometranscriptome sequencing
项目摘要
Increasing evidence implicates dysfunction of GABAergic interneurons in a host of neuropsychological condi-
tions, including autism, schizophrenia, bipolar disorder, and epilepsy. Recent success in identifying veritable
genetic risk factors together with the technological and methodological advances in human induced pluripotent
stem (iPS) cell-based models have rendered us a unique opportunity to develop in vitro human cellular models
for mechanistic investigations. Given the diversity of GABAergic interneurons, to move from the commonplace
idea that disturbed excitatory-inhibitory balance is associated with various neuropsychological conditions toward
a mechanistic understanding of the contribution of different interneuron subtypes to each unique pathophysiology,
it is essential to derive specific GABAergic cell types from human pluripotent stem cells (hPSCs). However, no
approach to date has been effective in generating homogeneous populations of specific GABAergic subtypes.
Our long-term goal is to develop and use human model systems to elucidate the molecular and cellular mecha-
nisms underlying GABAergic neuron dysfunction-associated neuropsychological disorders. As parvalbumin
(PV)- and somatostatin (SST)-expressing GABAergic interneurons originated from medial ganglionic eminence
(MGE) are known to be affected in autism, schizophrenia, and bipolar patients, the objective here is to generate
and characterize MGE-derived GABAergic neurons from human hPSCs. The central hypothesis of the current
study is that using a combination of external patterning factors and key lineage-determining transcription factors,
the differentiation of hPSCs can be precisely directed to produce distinct GABAergic cell types, which has been
formulated on the basis of previous studies and our largely unpublished Preliminary Data. The hypothesis will
be tested by pursuing two specific aims: 1) To guide human neural progenitor cell specification through sequen-
tial expression of neuron origin- and subtype-restricted key factors; 2) To transcriptionally specify human MGE
progenitors into GABAergic neuron subtypes. Under the first aim, we will mimic the genetic cascade that takes
place during development to specify GABAergic interneuron cell fate by ectopic expression of spatial and tem-
poral specific transcription factors in forebrain progenitors derived from hPSCs. Under the second aim, we will
transcriptionally specify MGE progenitor cells generated using different methods through ectopic expression of
PV- and SST-expressing GABAergic interneuron specific factors. A multidisciplinary approach will be used to
characterize the identity, heterogeneity, maturation stage and function of neurons generated. Applied together,
these aims will allow us to use previously established methods as a starting point and develop new approaches
that combine extrinsic factors and intrinsic transcriptional specifications to generate specific GABAergic cell types
from human PSCs. Given the high prevalence of PV- and SST-expressing GABAergic interneuron dysfunction
in neuropsychological disorders, this work will provide the fundamental tool for future studies that have the po-
tential to shed light on the key molecular and cellular mechanisms underlying these complex disease conditions.
越来越多的证据表明,GABA能中间神经元在许多神经心理条件下功能障碍,
包括自闭症、精神分裂症、躁郁症和癫痫。最近成功地查明了
遗传风险因素以及人类诱导多能干细胞的技术和方法学进展
基于干细胞(iPS)的模型为我们提供了开发体外人类细胞模型的独特机会
进行机械研究。鉴于GABA能中间神经元的多样性,
兴奋-抑制平衡紊乱与各种神经心理学状况有关,
对不同中间神经元亚型对每个独特病理生理学的贡献的机械理解,
从人多能干细胞(hPSC)中获得特定的GABA能细胞类型是必要的。但没有
迄今为止,一种方法在产生特异性GABA能亚型的同质群体中是有效的。
我们的长期目标是开发和使用人类模型系统来阐明分子和细胞机制,
GABA能神经元功能障碍相关的神经心理障碍的基础。作为小清蛋白
(PV)-和生长抑素(SST)表达的GABA能中间神经元起源于内侧神经节隆起
(MGE)已知在自闭症、精神分裂症和双相情感障碍患者中受到影响,这里的目标是产生
并表征来自人hPSC的MGE衍生的GABA能神经元。当前的核心假设是
研究表明,使用外部模式因子和关键谱系决定转录因子的组合,
hPSC的分化可以被精确地定向以产生不同的GABA能细胞类型,
根据以前的研究和我们基本上未发表的初步数据制定。假设将
通过追求两个具体目标进行测试:1)通过序列引导人类神经祖细胞特化,
神经元来源和亚型限制性关键因子的初步表达; 2)转录特异性人MGE
转化为GABA能神经元亚型。在第一个目标下,我们将模仿遗传级联,
在发育过程中的位置,通过空间和TEM的异位表达来指定GABA能中间神经元细胞的命运,
来源于hPSC的前脑祖细胞中的孔特异性转录因子。在第二个目标下,我们将
使用不同方法通过异位表达MGE基因产生转录特异性MGE祖细胞,
PV和SST表达GABA能中间神经元特异性因子。将采用多学科方法,
表征所产生的神经元的同一性、异质性、成熟阶段和功能。合在一起,
这些目标将使我们能够利用以前建立的方法作为起点,并开发新的方法
其结合联合收割机外在因子和内在转录规范以产生特定的GABA能细胞类型
从人类PSC中分离出来。考虑到PV和SST表达GABA能中间神经元功能障碍的高患病率,
在神经心理障碍中,这项工作将为未来的研究提供基本工具,
有可能揭示这些复杂疾病的关键分子和细胞机制。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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{{ truncateString('Nan Yang', 18)}}的其他基金
Functional mapping of noncoding regulatory variants in human neuronal subtypes
人类神经元亚型非编码调控变异的功能图谱
- 批准号:
10593976 - 财政年份:2022
- 资助金额:
$ 21.19万 - 项目类别:
Functional mapping of noncoding regulatory variants in human neuronal subtypes
人类神经元亚型非编码调控变异的功能图谱
- 批准号:
10416448 - 财政年份:2022
- 资助金额:
$ 21.19万 - 项目类别:
Cellular and molecular mechanisms of brain dysfunction in NF1
NF1脑功能障碍的细胞和分子机制
- 批准号:
10347337 - 财政年份:2020
- 资助金额:
$ 21.19万 - 项目类别:
Cellular and Molecular Mechanisms of Brain Dysfunction in NF1
NF1 脑功能障碍的细胞和分子机制
- 批准号:
10577861 - 财政年份:2020
- 资助金额:
$ 21.19万 - 项目类别:
Determining neuroprotective autophagy functions using different types of human neurons
使用不同类型的人类神经元确定神经保护自噬功能
- 批准号:
9974891 - 财政年份:2020
- 资助金额:
$ 21.19万 - 项目类别:
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