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

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

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FLORA M VACCARINO其他文献

FLORA M VACCARINO的其他文献

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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:
Neurobiology of Autism With Macrocephaly
自闭症大头畸形的神经生物学
  • 批准号:
    10358894
  • 财政年份:
    2021
  • 资助金额:
    $ 31.73万
  • 项目类别:
Neurodevelopment of Tourette syndrome
抽动秽语综合症的神经发育
  • 批准号:
    10529308
  • 财政年份:
    2019
  • 资助金额:
    $ 31.73万
  • 项目类别:
Neurodevelopment of Tourette syndrome
抽动秽语综合征的神经发育
  • 批准号:
    10302287
  • 财政年份:
    2019
  • 资助金额:
    $ 31.73万
  • 项目类别:
Neurodevelopment of Tourette syndrome
抽动秽语综合症的神经发育
  • 批准号:
    10063046
  • 财政年份:
    2019
  • 资助金额:
    $ 31.73万
  • 项目类别:
Neurobiology of Autism With Macrocephaly
自闭症大头畸形的神经生物学
  • 批准号:
    9479337
  • 财政年份:
    2017
  • 资助金额:
    $ 31.73万
  • 项目类别:
Neurobiology of Autism With Macrocephaly
自闭症大头畸形的神经生物学
  • 批准号:
    9920231
  • 财政年份:
    2016
  • 资助金额:
    $ 31.73万
  • 项目类别:
Neurobiology of Autism With Macrocephaly
自闭症大头畸形的神经生物学
  • 批准号:
    9320715
  • 财政年份:
    2016
  • 资助金额:
    $ 31.73万
  • 项目类别:
Neurobiology of Autism With Macrocephaly
自闭症大头畸形的神经生物学
  • 批准号:
    9082166
  • 财政年份:
    2016
  • 资助金额:
    $ 31.73万
  • 项目类别:

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了解 ADHD 的早期因果路径:早期出现的活动和影响的非典型性是否会导致后来出现的注意力困难?
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  • 批准号:
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