Neurobiology of Autism With Macrocephaly

自闭症大头畸形的神经生物学

基本信息

  • 批准号:
    9082166
  • 负责人:
  • 金额:
    $ 61.45万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-07-22 至 2021-04-30
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Autism spectrum disorders (ASDs) affect 1%-2.5% of children worldwide. We suggest that etiological and genetic heterogeneity might converge in a few neurobiological downstream pathways. We have been investigating the pathobiology of ASD with large brain volume (macrocephaly), a phenotype which confers poorer prognosis. Ongoing studies have shown that telencephalic organoids differentiated in vitro from induced pluripotent stem cells (iPSC) derived from patients with ASD and macrocephaly have increased cell proliferation, increased synaptic growth and overproduction of GABAergic inhibitory neurons, indicating an early imbalance in glutamate/GABA neuron ratio. RNA interference experiments suggested that the overproduction of GABAergic cells is attributable, at least in part, to an increase in expression of FOXG1, a master regulatory transcription factor crucial for telencephalic development. Major goals of this application are (1) to expand our analysis of the developmental pathways that are dysregulated in ASD to a larger number of families and (2) to understand to what extent developmental alterations we identified in ASD with macrocephaly also apply to ASD in general. To this end, we will obtain data on neurobiological measures, transcriptome and chromatin active regions in organoids derived from ASD patients with enlarged brain size and ASD patients with normal brain size. The altered gene regulatory network will be inferred and the two networks will be compared to understand similarities and differences in the two subgroups of ASD. To begin to understand the upstream causes of these developmental alterations, we will then investigate whether patients with ASD carry an increased burden of rare genomic variations in regions of the genome that participate in this regulatory network. Finally we will perform overexpression and RNAi knockdown experiments to examine the specific role of our current best candidate transcription factor, FOXG1, in the constellation of neurobiological and transcriptome alterations found in ASD-derived progenitors. We will assess the impact of perturbing FOXG1 gene expression on neurobiological functions (cell proliferation, glutamate/GABA neuron fate, synaptic growth), transcriptome and activity of transcription regulatory regions by RNA-seq and ChIP-seq, respectively, to gain insights into the role of a FOXG1-driven transcriptional program in the aberrant neuronal differentiation of ASD-derived neural progenitors. In summary, in this application we delineate strategies for (1) identifying gene networks and biological pathways that characterize altered development in two subgroups of ASD; (2) testing the causal role of one crucial node in such networks, the transcription factor FOXG1, which is over- active in ASD with macrocephaly; and (3) identifying regulatory factors, both genetic and epigenetic, upstream from neurobiological and gene expression abnormalities. The impact of these experiments will be the definition of a number of biological functions and molecular markers that are implicated in the neurobiology of ASD.
 描述(由申请人提供):自闭症谱系障碍(ASD)影响全球1%-2.5%的儿童。我们认为,病因和遗传异质性可能会收敛在一些神经生物学下游途径。我们一直在研究ASD的病理生物学与大脑容量(大头畸形),一个表型,赋予较差的预后。正在进行的研究表明,从ASD和大头畸形患者的诱导多能干细胞(iPSC)体外分化的端脑类器官具有增加的细胞增殖,增加的突触生长和GABA能抑制性神经元的过度产生,表明谷氨酸/GABA神经元比例的早期失衡。RNA干扰实验表明,GABA能细胞的过度产生至少部分归因于FOXG 1表达的增加,FOXG 1是一种对端脑发育至关重要的主调节转录因子。本申请的主要目标是(1)将我们对ASD中失调的发育途径的分析扩展到更多的家庭,以及(2)了解我们在患有大头畸形的ASD中鉴定的发育改变在多大程度上也适用于ASD。为此,我们将获得来自脑体积增大的ASD患者和脑体积正常的ASD患者的类器官中的神经生物学测量、转录组和染色质活性区域的数据。将推断改变的基因调控网络,并将两个网络进行比较,以了解ASD的两个亚组的相似性和差异。为了开始了解这些发育改变的上游原因,我们将研究ASD患者是否在参与该调控网络的基因组区域中携带增加的罕见基因组变异负担。最后,我们将进行过表达和RNAi敲低实验,以检查我们目前最好的候选转录因子FOXG 1在ASD衍生祖细胞中发现的神经生物学和转录组改变的星座中的特定作用。我们将分别通过RNA-seq和ChIP-seq评估干扰FOXG 1基因表达对神经生物学功能(细胞增殖,谷氨酸/GABA神经元命运,突触生长),转录组和转录调控区活性的影响,以深入了解FOXG 1驱动的转录程序在ASD衍生神经祖细胞异常神经元分化中的作用。总之,在本申请中,我们描述了用于以下的策略:(1)鉴定表征ASD的两个亚组中改变的发育的基因网络和生物学途径;(2)测试在这样的网络中的一个关键节点的因果作用,转录因子FOXG 1,其在具有大头畸形的ASD中过度活跃;和(3)鉴定神经生物学和基因表达异常上游的遗传和表观遗传调节因子。这些实验的影响将是ASD神经生物学中涉及的许多生物学功能和分子标志物的定义。

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:
    $ 61.45万
  • 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:
    $ 61.45万
  • 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:
    $ 61.45万
  • 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:
    $ 61.45万
  • 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:
    $ 61.45万
  • 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:
    $ 61.45万
  • 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:
    $ 61.45万
  • 项目类别:
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
  • 批准号:
    10240561
  • 财政年份:
    2017
  • 资助金额:
    $ 61.45万
  • 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:
    $ 61.45万
  • 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:
    $ 61.45万
  • 项目类别:

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加速磁共振弹性成像用于经典自闭症儿童脑僵硬分析
  • 批准号:
    10223915
  • 财政年份:
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加速磁共振弹性成像用于经典自闭症儿童脑僵硬分析
  • 批准号:
    10457950
  • 财政年份:
    2020
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Development of PC driven concept learning and achievement evaluation system for the children with autistic disorder
PC驱动的自闭症儿童概念学习和成绩评估系统的开发
  • 批准号:
    25590285
  • 财政年份:
    2013
  • 资助金额:
    $ 61.45万
  • 项目类别:
    Grant-in-Aid for Challenging Exploratory Research
Evaluation of Autistic Disorder using Artificial School Class Game
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  • 批准号:
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  • 财政年份:
    2011
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DENSE MAPPING OF CANDIDATE REGIONS LINKED TO AUTISTIC DISORDER
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DENSE MAPPING OF CANDIDATE REGIONS LINKED TO AUTISTIC DISORDER
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  • 财政年份:
    2009
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    $ 61.45万
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OPEN LABEL RISPERIDONE IN CHILDREN AND ADOLESCENTS WITH AUTISTIC DISORDER
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  • 批准号:
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    2009
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DENSE MAPPING OF CANDIDATE REGIONS LINKED TO AUTISTIC DISORDER
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  • 财政年份:
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sensorimotor gating processing in autistic disorder ; functional magnetic resonance imaging study
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  • 批准号:
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