Assessing Genomic, Regulatory and Transcriptional Variation at Single Nuclei Resolution in the Brains of Individuals with Autism Spectrum Disorder
评估自闭症谱系障碍患者大脑中单核分辨率的基因组、调控和转录变异
基本信息
- 批准号:10457436
- 负责人:
- 金额:$ 74.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-27 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalATAC-seqAffectAgeAnteriorAutopsyBRAIN initiativeBioinformaticsBiological AssayBiological MarkersBiological ModelsBiologyBrainBrain DiseasesBrain regionCell Culture TechniquesCell NucleusCell modelCell physiologyCellsCensusesChildChromatinCollaborationsCommunicationCorpus striatum structureCytoskeletonDNADNA Sequence AlterationDataData SetDevelopmentDiagnosticDiseaseEtiologyExhibitsExperimental ModelsFutureGene ExpressionGene Expression ProfileGene Expression RegulationGene FrequencyGenesGeneticGenetic DiseasesGenetic ModelsGenetic TranscriptionGenomicsGenotypeGenotype-Tissue Expression ProjectGoalsHeritabilityHeterogeneityHumanHuman GeneticsIn Situ HybridizationIndividualLentivirusMethodsModalityModelingMolecularMolecular AnalysisMolecular ProfilingMutationNeurobiologyNeurodevelopmental DisorderNeuronsNeurosciencesNucleic Acid Regulatory SequencesOrganoidsPathologyPhenotypePilot ProjectsPluripotent Stem CellsPrefrontal CortexProcessProtein IsoformsProtocols documentationRNA SplicingReporterResearchResolutionRisk FactorsRodentSample SizeSamplingSecond Pregnancy TrimesterSeizuresSingle Nucleotide PolymorphismSmall Nuclear RNASourceSpliced GenesStatistical Data InterpretationSyndromeSystems AnalysisTechniquesTestingTherapeuticTissue SampleTissuesUntranslated RNAValidationVariantWorkautism spectrum disorderbasebiobankbrain cellbrain tissuecase controlcell typecomorbidityde novo mutationdiagnostic signaturedifferential expressionexperiencefunctional genomicsfunctional groupgenetic analysisgenetic disorder diagnosisgenetic risk factorgenetic variantgenome sequencinggenomic datagenomic locushuman modelindividuals with autism spectrum disorderinsertion/deletion mutationinsightloss of function mutationneuropsychiatric disorderpolygenic risk scorerepositorysexstem cell modelstem cellstherapeutically effectivetranscriptome sequencingtranscriptomicswhole genome
项目摘要
ABSTRACT
Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder of unknown etiology and with
limited effective therapeutic options that affects millions of individuals. Our research team has a longstanding
commitment to understanding the cause of ASD and the molecular processes underlying brain development,
function, and pathology. We will use this experience to apply the latest molecular techniques to samples from a
new repository of brain tissue from individuals with ASD to create the largest and most detailed analysis of the
molecular consequences of ASD. Genetic analyses of gene disrupting de novo mutations have identified over
one hundred genes associated with ASD with three main functional groups: regulation of gene expression,
neuronal communication, and cytoskeleton. Prior analyses of brain tissue from individuals with ASD have
identified a group of downregulated neuronal communication genes, that overlap with ASD-associated genes,
and a group of upregulated glial genes that do not overlap with ASD-associated genes or variants. It is unclear
if these changes reflect altered cell composition or cell function and how they relate to genetic factors. We
propose to analyze post-mortem brain samples from 40 individuals with ASD and 40 unaffected controls, sourced
from the Autism BrainNet BioBank, to assess the molecular changes that occur. We will use whole-genome
sequencing to identify gene disruptive variants in genes previously associated with ASD and to identify rare and
common variants that may alter gene expression or splicing. In tissue samples the prefrontal cortex and striatum
in from 40 cases and 40 controls, we will use recently developed single-nuclei methods to perform RNA-seq and
ATAC-seq at single-cell resolution to identify ASD-related changes in gene regulation and expression in specific
cell types and brain regions. For tissue samples from the prefrontal cortex of 20 cases and 20 controls we will
also use cutting-edge single nuclei long-read RNA-seq (Iso-seq), along with bulk tissue RNA-seq, for an in-depth
analysis of how gene isoforms differ between ASD cases and controls. Finally, we will assess how single-nuclei
gene expression varies in brain organoids grown from pluripotent stem cells edited to contain mutations in three
ASD-associated genes. Integrating these data, we will profile the molecular changes associated with ASD and
assess how these changes vary by cell type, brain region, age, sex, seizure status, and genotype. We will use
RNAscope in situ hybridization to validate the molecular and cell composition changes we observe and a
lentivirus-based massively parallel reporter assay to test the function of regulatory regions or variants in proximity
to genes with ASD-related differences in expression to validate these effects and assess causality. We hope that
these insights will provide a basis for understanding the heterogeneity of ASD and the neurobiological features
of this disorder and provide molecular signatures that could be developed into future biomarkers for ASD model
systems.
摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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ARNOLD KRIEGSTEIN其他文献
ARNOLD KRIEGSTEIN的其他文献
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{{ truncateString('ARNOLD KRIEGSTEIN', 18)}}的其他基金
Assessing Genomic, Regulatory and Transcriptional Variation at Single Nuclei Resolution in the Brains of Individuals with Autism Spectrum Disorder
评估自闭症谱系障碍患者大脑中单核分辨率的基因组、调控和转录变异
- 批准号:
10657693 - 财政年份:2021
- 资助金额:
$ 74.99万 - 项目类别:
Assessing Genomic, Regulatory and Transcriptional Variation at Single Nuclei Resolution in the Brains of Individuals with Autism Spectrum Disorder
评估自闭症谱系障碍患者大脑中单核分辨率的基因组、调控和转录变异
- 批准号:
10317710 - 财政年份:2021
- 资助金额:
$ 74.99万 - 项目类别:
Charting the 3D epigenome in human brain development and diseases
绘制人类大脑发育和疾病中的 3D 表观基因组图
- 批准号:
10685257 - 财政年份:2020
- 资助金额:
$ 74.99万 - 项目类别:
Charting the 3D epigenome in human brain development and diseases
绘制人类大脑发育和疾病中的 3D 表观基因组图
- 批准号:
10116735 - 财政年份:2020
- 资助金额:
$ 74.99万 - 项目类别:
Charting the 3D epigenome in human brain development and diseases
绘制人类大脑发育和疾病中的 3D 表观基因组图
- 批准号:
10267777 - 财政年份:2020
- 资助金额:
$ 74.99万 - 项目类别:
Development and Expansion of the Human Cerebral Cortex
人类大脑皮层的发育和扩展
- 批准号:
9481453 - 财政年份:2017
- 资助金额:
$ 74.99万 - 项目类别:
Development and Expansion of the Human Cerebral Cortex
人类大脑皮层的发育和扩展
- 批准号:
10531270 - 财政年份:2016
- 资助金额:
$ 74.99万 - 项目类别:
Development and Expansion of the Human Cerebral Cortex
人类大脑皮层的发育和扩展
- 批准号:
10539676 - 财政年份:2016
- 资助金额:
$ 74.99万 - 项目类别:
Development and Expansion of the Human Cerebral Cortex
人类大脑皮层的发育和扩展
- 批准号:
9160977 - 财政年份:2016
- 资助金额:
$ 74.99万 - 项目类别:
Development and Expansion of the Human Cerebral Cortex
人类大脑皮层的发育和扩展
- 批准号:
10061656 - 财政年份:2016
- 资助金额:
$ 74.99万 - 项目类别:
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