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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：
9320715
负责人：
FLORA M VACCARINO
金额：
$ 58.77万
依托单位：
YALE UNIVERSITY
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

来源：
https://reporter.nih.gov/project-details/9320715
关键词：
Affect Autistic Disorder Binding Sites Biological Biological Assay Biological Process Brain Cell Adhesion Cell Line Cell Proliferation Cell division Cells ChIP-seq Child Chromatin Code Collection DNA Sequence Alteration Data Data Set Development Electrophysiology (science)Epigenetic Process Etiology FOXG1B gene Family First Pregnancy Trimester Forebrain Development Future Gene Expression Genes Genetic Genetic Heterogeneity Genetic Transcription Genome Genomic Segment Genotype Glutamates Goals Growth Heterogeneity Histones Human In Vitro Individual Inherited Macrocephaly Maps Measures Neurobiology Neuronal Differentiation Neurons Nucleic Acid Regulatory Sequences Organoids Pathogenesis Pathway Analysis Pathway interactions Patients Phenotype Proteins RNA Interference Regulator Genes Role Source Structure Subgroup Synapses Technology Testing Therapeutic Untranslated RNA Validation Variant autism spectrum disorder brain size brain volume differential expression experimental study gamma-Aminobutyric Acid genetic variant genome sequencing genome-wide genomic variation induced pluripotent stem cell inhibitory neuron insight knock-down molecular marker nerve stem cell neurodevelopment outcome forecast overexpression patient subsets proband progenitor programs public health relevance rare variant structural genomics synaptogenesis trait transcription factor transcriptome transcriptome sequencing whole genome

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.