Common schizophrenia variants functioning in developmental human cortical interneurons
在发育中的人类皮质中间神经元中发挥作用的常见精神分裂症变异
基本信息
- 批准号:10735990
- 负责人:
- 金额:$ 81.27万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-01 至 2028-04-30
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalATAC-seqAddressAdultAffectAutopsyBiologicalBrainCRISPR interferenceCRISPR-mediated transcriptional activationCellsChIP-seqChromatinChromosomesCodeComplementComplexDataData SetDevelopmentDevelopmental ProcessDiseaseDistalEarly identificationEmbryoEmbryonic DevelopmentFetal DevelopmentGene ExpressionGene Expression ProfileGenerationsGenesGeneticGenetic RiskGenetic studyGenomeGenomicsGenotypeGleanGoalsHeritabilityHumanIn VitroInterneuronsLibrariesMapsMedialMethodsMusNeurodevelopmental DisorderNeuronsParvalbuminsPathologicPathway interactionsPatientsPluripotent Stem CellsPopulationProceduresQualifyingQuantitative Trait LociRegulationRegulator GenesResolutionRoleSchizophreniaSomatostatinSynapsesTestingTimeTissuesTrainingTransplantationUntranslated RNAValidationVariantWeightWorkbrain cellbrain tissuecell typecohortfetalgene regulatory networkgenetic makeupgenome wide association studygenome-widehuman fetal brainin vivoinduced pluripotent stem cellinsightmigrationnew therapeutic targetrisk variantschizophrenia riskstem cell differentiationtranscription factortranscriptometranscriptome sequencingtranscriptomics
项目摘要
Abstract
Schizophrenia (SCZ) is a highly heritable and complex neurodevelopmental disorder. Remarkable advances
have been made recently in SCZ genetic studies with an increasing number of risk loci reaching genome-wide
significance; however, gleaning biological insight from these loci has been challenging. The majority of SCZ risk
loci are located in non-coding regions. As such, it is hypothesized that they function by regulating distal gene
expression via 3D chromatin interactions. However, it has yet to be determined which loci are operational in
which cells, at what time points, and with what impact. Recent genomic analyses showed enriched SCZ
heritability in human fetal brains rather than adult brains, suggesting the role of SCZ risk loci in modulating fetal
development for increased SCZ risks. Thus, unraveling SCZ risk loci function during development will be critical
for understanding genetic influences on SCZ risks. Genetic influences on gene expression (e.g. expression
quantitative trait loci (eQTLs)) are cell-type-specific, and sometimes confer opposing effects depending on the
cell type, underscoring the importance of cell-type-specific studies using homogeneous cell populations for a
clear mechanistic understanding. Parvalbumin (PV)- or somatostatin (SST)-expressing medial ganglionic
eminence (MGE)-derived cortical interneurons (cINs) are consistently affected in SCZ brains. More importantly,
SCZ heritability is shown to be enriched in MGE cells in human fetal brains, necessitating the study of these
cells to understand the mechanisms of SCZ risk loci. Although there are no postmortem fetal SCZ tissues for
mechanistic study, in vitro differentiation of iPSC—which well recapitulates early embryonic development—
provides developmental SCZ brain cells with the same genetic makeup as patient brains. We established
methods for the efficient generation of homogeneous populations of MGE-derived cINs from healthy control
(HC) and SCZ iPSCs. We also extensively validated their functionality and authenticity both in vitro and in vivo,
including robust migration and synaptic integration into host brains that results in efficient inhibitory regulation of
host circuitry in transplanted mice. Using an unprecedentedly large number of iPSCs to provide homogeneous
populations of HC vs SCZ fetal cINs for mechanistic studies, we will address our hypothesis that SCZ risk loci
active in developmental MGE-type cINs regulate distal gene expression via 3D chromatin interactions.
Employing transcriptome analysis, PrediXcan analysis, and Micro-C analysis, we will map SCZ risk loci with
unknown functions to the risk genes they regulate in these vulnerable cell populations during development.
Developmental cIN-specific genetic influences on gene expression, identified based on multiple lines of
corroborating evidence, will be functionally validated using CRISPRi/CRISPRa approaches. This unbiased
genome-wide comprehensive data set from developmental MGE-type cINs with functional validation will provide
a road map for unravelling the genetic basis of developmental SCZ risks and help us identify mechanism-based
novel therapeutic targets.
抽象的
精神分裂症(SCZ)是一种高度遗传和复杂的神经发育障碍。出色的进步
最近在SCZ遗传研究中进行了,风险基因座越来越多地达到全基因组
意义;但是,从这些基因座中收集的生物学见解一直是挑战。大多数SCZ风险
局部位于非编码区域。因此,假设它们通过调节远端基因发挥作用
通过3D染色质相互作用表达。但是,它尚未确定哪个本地运作
哪些细胞在什么时间点以及影响什么。最近的基因组分析表明SCZ富集
人类胎儿大脑而不是成年大脑的遗传力,这表明SCZ风险基因座在调节胎儿中的作用
SCZ风险增加的发展。那就是开发过程中阐明SCZ风险基因座功能至关重要
了解遗传对SCZ风险的影响。遗传对基因表达的影响(例如表达
定量性状局部(eqtls))是细胞类型特异性的,有时会根据相反的影响
细胞类型,强调了使用均质细胞群的细胞类型研究的重要性
清晰的机械理解。白蛋白(PV) - 或生长抑素(SST) - 表达内侧神经节
在SCZ大脑中,杰出(MGE)衍生的皮质中间神经元(CIN)始终受到影响。更重要的是,
SCZ的遗传力显示出富含人类胎儿大脑中的MGE细胞,需要研究这些细胞
细胞了解SCZ风险基因座的机制。尽管没有验尸后胎儿SCZ组织
机械研究,IPSC的体外分化,这很好地概括了早期胚胎发育 -
提供与患者大脑相同的基因组成的发育SCZ脑细胞。我们建立了
从健康控制中有效生成MGE衍生CIN的均质种群的方法
(HC)和SCZ IPSC。我们还广泛验证了它们在体外和体内的功能和真实性,
包括强大的迁移和突触整合到宿主的大脑中,从而导致有效的抑制性调节
移植小鼠中的宿主电路。使用前所未有的大量IPSC提供同质
HC与SCZ胎儿CIN的种群用于机械研究,我们将解决SCZ风险基因座的假设
活跃于发育的MGE型CINS通过3D染色质相互作用调节盘式基因表达。
采用转录组分析,prepixcan分析和Micro-C分析,我们将与SCZ风险基因座绘制
在开发过程中,它们在这些脆弱的细胞种群中调节的风险基因的功能未知。
发育性CIN特异性的通用影响对基因表达,根据多个行鉴定
可证实的证据将在功能上使用CRISPRI/CRISPRA方法在功能上进行验证。这个公正
来自具有功能验证的发育性MGE型CIN的全基因组全面数据集将提供
开发SCZ风险的遗传基础的路线图,并帮助我们确定基于机制
新型治疗靶标。
项目成果
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SANGMI CHUNG其他文献
SANGMI CHUNG的其他文献
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{{ truncateString('SANGMI CHUNG', 18)}}的其他基金
Brain-region-specific humanized cortical interneuron mice
脑区域特异性人源化皮质中间神经元小鼠
- 批准号:
10735991 - 财政年份:2023
- 资助金额:
$ 81.27万 - 项目类别:
Stem Cell-Derived Developmental Human Cortical Interneurons to Treat Intractable Epilepsy
干细胞衍生的发育性人类皮质中间神经元治疗难治性癫痫
- 批准号:
10355921 - 财政年份:2021
- 资助金额:
$ 81.27万 - 项目类别:
iPSC derived human cortical interneurons as developmental model of Schizophrenia
iPSC 衍生的人类皮质中间神经元作为精神分裂症的发育模型
- 批准号:
8944687 - 财政年份:2015
- 资助金额:
$ 81.27万 - 项目类别:
Isolation and characterization of midbrain dopaminergic neuronal precursors
中脑多巴胺能神经元前体的分离和表征
- 批准号:
8494704 - 财政年份:2012
- 资助金额:
$ 81.27万 - 项目类别:
Isolation and characterization of midbrain dopaminergic neuronal precursors
中脑多巴胺能神经元前体的分离和表征
- 批准号:
8356550 - 财政年份:2012
- 资助金额:
$ 81.27万 - 项目类别:
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