Developmental Timing During Cortical Development
皮质发育期间的发育时间
基本信息
- 批准号:10446603
- 负责人:
- 金额:$ 41.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-05-01 至 2027-04-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAdultAnatomyAreaAstrocytesBar CodesBiological ModelsBrainCRISPR/Cas technologyCell Differentiation processCell LineageCellsCerebral cortexCharacteristicsClone CellsComparative StudyCompetenceDNA Sequence AlterationDataDevelopmentEventExperimental ModelsFerretsFiberFoundationsGene ExpressionGenerationsGenesGeneticGoalsGrantHeterogeneityHumanIndividualKnowledgeMental disordersMethodsModelingMolecularMorphologyMusMutationNeurodevelopmental DisorderNeurogliaNeuronsNewborn InfantOligodendrogliaPathway interactionsPatternPhenotypePregnancyPrimatesProductionProtoplasmic AstrocyteRadialResourcesRodentSecond Pregnancy TrimesterSeriesSliceSpecific qualifier valueSwellingTCF7L2 geneTechnologyTestingTimeTransplantationVentricularViralWorkXenograft procedureZIKV infectionbrain tissuecell fate specificationcell typedevelopmental neurobiologyexperimental studyhuman tissuein silicoin vivoinnovationinnovative technologiesknock-downmolecular markermolecular subtypesneonatal brainneonatal micenerve stem cellneuroepitheliumprogenitorsingle cell mRNA sequencingsingle cell sequencingstem cellssubventricular zonetooltranscription factortranscriptomics
项目摘要
Summary/Abstract
The human cerebral cortex contains an astonishing diversity of cell types distributed across dozens of
functional areas, which emerge during early development for an apparently uniform neuroepithelium. It has long
been hypothesized that genetic mutations underlying brain development abnormalities and genes implicated in
neurodevelopmental psychiatric disorders can impact brain development in a variety of ways, but we currently
lack scalable tools for interrogating their impact on the development of specialized cell types.
Astrocytes represent a highly diverse cell class that is broadly categorized into a handful of cardinal types.
Astrocytes emerge in late development, and selective vulnerabilities of astrocyte subtypes to mutations or
environmental perturbations may underlie distinct phenotypes in psychiatric disorders or in Zika virus infection.
However, developmental origins, molecular characteristics, and mechanisms of subtype specification are poorly
understood. We currently lack experimental methods to study human astrocyte subtypes and their development.
Our preliminary data suggest that at mid-gestation, radial glia subtypes may be biased towards generating
different subtypes of human astrocytes. In the proposed project we propose to extend this finding by mapping
the temporal dynamics of cellular differentiation from radial glia subtypes across multiple stages of development.
We will also determine whether similar developmental dynamics take place in ferret, which could serve as a
substitute to human tissue and enable in vivo functional studies.
Secondly, we will determine developmental lineage relationships between cortical radial glia subtypes and
astrocyte subtypes. Our preliminary studies predict morphologically distinct subtypes of astrocytes emerge from
anatomically distinct germinal niches, and we propose to directly register these morphotypes to transcriptomic
identities using single cell mRNA sequencing.
Finally, our goal is to understand whether distinct radial glia subtypes contribute distinct cell types of the
cerebral cortex. To address this question, we propose to perform xenotransplantation experiments into mouse
brain. We will combine this approach with single cell sequencing, and in silico analyses co-embedding our data
with existing resources from adult human cortex to reveal what molecular subtypes may emerge from
transcriptomically- distinct subtypes of cortical progenitor cells.
摘要/摘要
人类大脑皮层包含了惊人的细胞类型的多样性,分布在几十个
功能区,其在早期发育过程中出现,用于明显均匀的神经上皮。长期
据推测,大脑发育异常的基因突变和与大脑发育异常有关的基因,
神经发育性精神障碍可以以多种方式影响大脑发育,但我们目前
缺乏可扩展的工具来询问它们对特化细胞类型发育的影响。
星形胶质细胞代表了一个高度多样化的细胞类别,其被广泛地分类为少数主要类型。
星形胶质细胞出现在发育后期,星形胶质细胞亚型对突变或突变的选择性脆弱性。
环境扰动可能是精神疾病或寨卡病毒感染中不同表型的基础。
然而,发育起源、分子特征和亚型特化机制尚不清楚,
明白我们目前缺乏实验方法来研究人类星形胶质细胞亚型及其发展。
我们的初步数据表明,在妊娠中期,放射状胶质细胞亚型可能偏向于产生
不同亚型的人类星形胶质细胞在建议的项目中,我们建议通过映射来扩展这一发现
放射状胶质细胞亚型在多个发育阶段的细胞分化的时间动态。
我们还将确定在雪貂中是否发生类似的发育动力学,这可以作为一种研究方法。
替代人体组织并能够进行体内功能研究。
其次,我们将确定皮质放射状胶质细胞亚型之间的发育谱系关系,
星形胶质细胞亚型我们的初步研究预测,星形胶质细胞的形态学上不同的亚型出现,
解剖学上不同的生殖器小生境,我们建议直接注册这些形态类型的转录组学
使用单细胞mRNA测序鉴定。
最后,我们的目标是了解不同的放射状胶质细胞亚型是否有助于不同的细胞类型,
大脑皮层为了解决这个问题,我们建议进行异种移植实验到小鼠,
个脑袋我们将联合收割机与单细胞测序和计算机分析结合起来,共同嵌入我们的数据
与现有的成人大脑皮层资源,揭示什么分子亚型可能出现,
转录组学上不同的皮质祖细胞亚型。
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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Tomasz Nowakowski其他文献
Tomasz Nowakowski的其他文献
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{{ truncateString('Tomasz Nowakowski', 18)}}的其他基金
Neurodevelopmental defects of the thalamocortical pathway as a convergent feature of psychiatric disorders
丘脑皮质通路的神经发育缺陷是精神疾病的共同特征
- 批准号:
10655225 - 财政年份:2023
- 资助金额:
$ 41.26万 - 项目类别:
Directed Evolution of Novel AAVs and Regulatory Elements for Selective Microglial Gene Expression
新型 AAV 和选择性小胶质细胞基因表达调控元件的定向进化
- 批准号:
10587795 - 财政年份:2023
- 资助金额:
$ 41.26万 - 项目类别:
Developmental Timing During Cortical Development
皮质发育期间的发育时间
- 批准号:
10613569 - 财政年份:2022
- 资助金额:
$ 41.26万 - 项目类别:
Machine Learning Augmented Discovery of AAV Capsids for Cell Type Specific Access into Human Neurons and Glia
机器学习增强了 AAV 衣壳的发现,用于特定细胞类型进入人类神经元和神经胶质细胞
- 批准号:
10512547 - 财政年份:2022
- 资助金额:
$ 41.26万 - 项目类别:
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