Gene expression profiling of IPSC derived neurons in Autism Spectrum Disorder
自闭症谱系障碍中 IPSC 衍生神经元的基因表达谱
基本信息
- 批准号:10320346
- 负责人:
- 金额:$ 73.73万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-04-06 至 2022-12-31
- 项目状态:已结题
- 来源:
- 关键词:ASD patientAccountingAffectAgeArchitectureAutism DiagnosisAutomobile DrivingAutopsyBiologicalBiological AssayBiologyBrainCalciumCaliforniaCell LineCell SurvivalCellular AssayCollectionComplexCopy Number PolymorphismDataDerivation procedureDevelopmentDimensionsDiseaseExonsFrequenciesFundingGene ExpressionGene Expression ProfilingGenesGeneticGenomicsGenotypeGlutamatesHeterogeneityHumanImageIn VitroIndividualInduced pluripotent stem cell derived neuronsIndustrializationInstitutesInternationalInvestigationLengthMolecularMorphologyNeuritesNeurodevelopmental DisorderNeuronal DifferentiationNeuronsOutcomePathologyPathway AnalysisPathway interactionsPatientsPatternPeripheralPhenotypePopulationQuantitative Trait LociRNA analysisRegenerative MedicineReproducibilityResearch PersonnelRiskSamplingSeveritiesSingle Nucleotide PolymorphismSynapsesTimeTissuesTranscriptional RegulationVariantVial deviceagedautism spectrum disorderbehavioral phenotypingbiological systemscase controlchromatin remodelingclinical phenotypecostde novo mutationdifferential expressiondisorder controlexome sequencinggene discoverygenetic makeupgenomic locusin vivoindividuals with autism spectrum disorderinduced pluripotent stem cellinhibitory neuroninsightlive cell imagingneurodevelopmentpotential biomarkerrelating to nervous systemrisk variantsexsocialstem cell genestherapeutic targettranscriptometranscriptome sequencing
项目摘要
Autism Spectrum Disorder (ASD) is a genetically and phenotypically heterogeneous
neurodevelopmental disorder. Hundreds of genes contribute to the risk to develop ASD with no individual
genetic locus accounting for more than 1% of cases. This raises the issue of whether, and how such diverse
mechanisms converge on a smaller number of biological pathways that ultimately result in one phenotype,
namely ASD. The inability to study neurons and brains from living subjects has blocked progress toward
understanding the cellular and molecular mechanisms underlying ASD and other neurodevelopmental
disorders.
Neurons derived from human induced pluripotent stem cell (hiPSC) recapitulate multiple stages of in
vivo neural development in vitro. Because they retain the genetic makeup of the patient they enable in vitro
studies of neurons that harbor the complex genetic background associated with ASD. Deriving neurons from
hiPSCs is labor intensive and costly, and to date studies have examined very small numbers of patients.
hiPSC studies of the scope required to capture idiopathic ASD have not been possible, entirely limiting our
ability to determine the mechanistic underpinnings of this form of the disorder. We propose to conduct an
investigation of hiPSC derived neurons on an unprecedented scale by leveraging our California Institute for
Regenerative Medicine (CIRM) funded existing collection of over 300 hiPSCs, to examine 100 individuals with
idiopathic ASD and 100 age- and sex-matched controls. We will use commercially derived neurons (iCell
Neurons) which are a >95% pure population of glutamatergic (excitatory) and GABAergic (inhibitory) neurons.
To identify dysregulated molecular pathways in these neurons we will sequence the human transcriptome at
three time points during maturation of the neurons. We will also conduct assays of cell viability, morphology,
neurite outgrowth using live cell imaging, and function through calcium imaging. We aim to identify
dysregulated molecular pathways in these hiPSC-derived neurons from individuals with ASD, by identifying
genes that are differentially expressed from controls at each time point and perform a factorial analysis to study
interactive effects between time point and disease variable. This will identify genes showing differentiation-
induced expression changes across neuronal differentiation in individuals with ASD. We will identify key
drivers of biological pathway changes using Weighted Gene Co-expression Network Analysis (WGCNA).
Finally, we will relate gene expression profiles to cellular and behavioral phenotypes.
自闭症谱系障碍(ASD)是一种遗传和表型异质性的疾病
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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JOACHIM F HALLMAYER其他文献
JOACHIM F HALLMAYER的其他文献
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{{ truncateString('JOACHIM F HALLMAYER', 18)}}的其他基金
Integrated, cell type specific functional genomics analyses of regulatory sequence elements and their dynamic interaction networks in neuropsychiatric brain tissues
神经精神脑组织中调节序列元件及其动态相互作用网络的综合、细胞类型特异性功能基因组学分析
- 批准号:
10609543 - 财政年份:2019
- 资助金额:
$ 73.73万 - 项目类别:
Integrated, cell type specific functional genomics analyses of regulatory sequence elements and their dynamic interaction networks in neuropsychiatric brain tissues
神经精神脑组织中调节序列元件及其动态相互作用网络的综合、细胞类型特异性功能基因组学分析
- 批准号:
10411895 - 财政年份:2019
- 资助金额:
$ 73.73万 - 项目类别:
Integrated, cell type specific functional genomics analyses of regulatory sequence elements and their dynamic interaction networks in neuropsychiatric brain tissues
神经精神脑组织中调节序列元件及其动态相互作用网络的综合、细胞类型特异性功能基因组学分析
- 批准号:
10133146 - 财政年份:2019
- 资助金额:
$ 73.73万 - 项目类别:
Creation and Evaluation of iPSCs from Children with ASD with Megalencephaly
自闭症谱系障碍 (ASD) 巨脑畸形儿童 iPSC 的创建和评估
- 批准号:
10238008 - 财政年份:2017
- 资助金额:
$ 73.73万 - 项目类别:
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