Biological substrates of risk and resilience using patient-derived stem cells
使用患者来源干细胞的风险和复原力的生物基质
基本信息
- 批准号:10240561
- 负责人:
- 金额:$ 31.73万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-07 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAffectAttentionBiologicalBiologyBrainBrain imagingCell LineCell modelCellular StructuresCerebral cortexChildClinicalCollaborationsCopy Number PolymorphismDataDeltastabDevelopmentDiagnosisDisciplineDiseaseEarly DiagnosisFathersFetal DevelopmentFunctional ImagingFunding MechanismsFutureGene ExpressionGene Expression ProfileGene Expression ProfilingGenesGeneticGenetic RiskHumanImageIn VitroInhibitory SynapseLinkMacrocephalyMagnetic Resonance ImagingMeasuresModelingMolecularMutationNeurobiologyNeuronsOrganoidsPathway AnalysisPatient RecruitmentsPatientsPhenotypeProductionRestRiskRisk FactorsSeveritiesSiblingsStructureSymptomsSynapsesSyndromeWorkautism spectrum disorderautistic childrenbasecellular imagingclinical predictorscohortconnectomedensitydifferential expressiondisorder riskearly detection biomarkersexcitatory neuronexome sequencingfetalgray matterhigh resolution imaginghigh riskimaging approachin vitro Modelinduced pluripotent stem cellinhibitory neuronmalemolecular imagingneurodevelopmentpredict clinical outcomepredictive modelingprenatalprenatal disorderprobandprotective factorsresiliencestem cellssynaptogenesistooltranscriptometranscriptome sequencingtranscriptomicsvariant detectionwhite matter
项目摘要
Autism spectrum disorder (ASD) is a disorder of prenatal brain development. While syndromic forms of ASD
have received considerable attention, to what extent findings in these heterogeneous disorders apply also to
the broader or idiopathic form of ASD with no identified single genetic risk is unclear. In this project, we will
study how the normal trajectory of prenatal neurobiological development of the brain is disrupted in idiopathic
ASD. To identify neurobiological factors that are associated with risk or protection from ASD during prenatal
development, we will recruit participants from a well-characterized cohort of younger siblings of children with
ASD, who were followed longitudinally. The siblings will be either concordant for ASD diagnosis (ASD:ASD;
n=12 pairs) or will be discordant (ASD:TYP; n=12 pairs). We will use induced pluripotent stem cells (iPSC)
derived cortical organoids, 3D cellular structures which model in vitro the fetal development of the human
cerebral cortex. Organoids will be analyzed by high resolution imaging approaches, molecular tools and
transcriptomics. In Aim 1 we will obtain sets of biological measures (excitatory/inhibitory neuron fate, density of
synapse, and neuronal arborization), comparing and contrasting phenotypes between ASD:ASD concordant
sibs ASD:TYP discordant sibs. This comparison will refine our ability to isolate risk/protective factors that will
be exclusively at work in the discordant pairs. In Aim 2 we will perform global gene expression analysis by
RNA-seq and network analyses, aiming at finding differences in gene expression and network organization
between the ASD:ASD concordant network and the ASD:TYP discordant network. We will perform correlation
analyses where neurobiological measures and gene expression will be correlated with each other and with
clinical severity scores. The correlations between neurobiological and gene expression measures with
symptoms severity may help discriminate between risk and protection. In Aim 3, in collaboration with Project 2,
we will obtain structural MRI and BOLD-based functional connectivity data on the concordant (ASD:ASD) and
discordant (ASD:TYP) sib pairs that participate in Aim 1 and Aim 2 studies. We will then make correlations
between imaging and neurobiological and gene expression measures. We hypothesize that increased
inhibitory neuron fate in ASD may be correlated with less efficient cortical network connectivity and that
increased synaptogenesis and neuronal arborization may be correlated with higher gray matter ratio, and also
to altered connectivity. This project will feed data to the statistical core, where imaging and neurobiological
measures can be used to predict clinical severity, allowing a more powerful analysis of risk factors for ASD. In
summary, our in vitro ASD risk human cellular model will allow, in principle, to develop future biomarkers for
early diagnosis and the exploration of new treatment options based on the underlying biology.
自闭症谱系障碍(ASD)是一种产前大脑发育障碍。而自闭症的症候群
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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FLORA M VACCARINO其他文献
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{{ truncateString('FLORA M VACCARINO', 18)}}的其他基金
Sex-specific trajectories in epigenomic regulation of brain patterning
大脑模式表观基因组调控的性别特异性轨迹
- 批准号:
10419143 - 财政年份:2022
- 资助金额:
$ 31.73万 - 项目类别:
Sex-specific trajectories in epigenomic regulation of brain patterning
大脑模式表观基因组调控的性别特异性轨迹
- 批准号:
10610415 - 财政年份:2022
- 资助金额:
$ 31.73万 - 项目类别:
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