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
基本信息
- 批准号:10419143
- 负责人:
- 金额:$ 94.01万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-15 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAffectAlzheimer&aposs DiseaseAnteriorAttention deficit hyperactivity disorderAutopsyBiologicalBiological MarkersBrainCellsClinicalCodeCollectionDataData SetDevelopmentDiagnosticDiseaseDisease OutcomeDisease susceptibilityEmbryoEnhancersEpigenetic ProcessEventExtracellular MatrixFemaleFunctional disorderGene ExpressionGene Expression RegulationGene ProteinsGenesGeneticGenetic DiseasesGenetic Enhancer ElementGenetic RiskGilles de la Tourette syndromeGoalsGonadal Steroid HormonesHereditary DiseaseHumanHuman DevelopmentIncidenceIndividualInheritedKnowledgeLongitudinal StudiesModelingMolecularNeurodevelopmental DisorderOrganoidsOutcomePathogenicityPatternPeptidesPredispositionPrevalenceProteomeRegulationRegulator GenesRegulatory ElementResearch PersonnelResolutionRiskRisk FactorsSchizophreniaSeveritiesSeverity of illnessSex BiasSex DifferencesShapesTestingTimeTissue-Specific Gene ExpressionTissuesUntranslated RNAVariantWorkautism spectrum disorderbasecell typedesigndevelopmental diseasedisorder riskepigenomeepigenomicsfetalgene networkgene productgene regulatory networkgenetic risk factorgenetic variantgenome sequencinggenome wide association studygonad developmenthuman fetal braininduced pluripotent stem cellmalemultidisciplinaryoverexpressionprobandprogramsprotective factorsprotein expressionrisk variantsexsexual dimorphismtranscriptometranscriptome sequencingtreatment strategytrendvirtualwhole genome
项目摘要
The core concept of our proposed studies is that sex-biased gene expression early in human
development pattern the brain differently in males and females, and that this patterning underlies
differential susceptibility of males and females to neurodevelopmental disorders. We envision that
these sex differences are regulated by epigenetic programs controlling the expression of
developmentally regulated genes in a sex-biased manner. We further postulate that these sex-
dependent epigenetic mechanisms interact with genetic risk factors that influence risk,
progression, and severity of autism sprectrum disorders (ASD) and schizophrenia (SCZ), and we
will test these hypotheses in two specific aims. Aim 1 is to delineate the sex-dependent regulation
of early brain development in typical individuals. Epigenetic and gene expression programs in
brain organoids and postmortem fetal brains will be evaluated on multiple levels, including
transcriptome, proteome, and activity of noncoding regulatory elements. The objective of this aim
is to define a network of genes and their regulatory elements—primarily enhancers—that are
differentially active between males and females during early brain development. Aim 2 will
determine whether the sex-biased regulatory network carries an increased burden of potentially
pathogenic or risk associated genetic variants in developmental disorders such as SCZ and ASD.
We will query available genome sequencing and GWAS datasets of probands and typical controls
to determine whether the sex-biased regulatory network are enriched for rare and common
inherited disease variants. Enrichment of these variants in the sex-biased regulatory network will
reveal potential mechanisms by which sex-biased gene expression affects SCZ and ASD genetic
risk and trajectory. The impact of this work is seeking the first detailed understanding of early
sexually dimorphic brain development. The new knowledge will constitute a fundamental advance
in our understanding of normal development, and will pioneer the discovery of how disease
susceptibility depends on sex-biased gene regulation in the developing brain.
我们所提出的研究的核心概念是,性别偏见的基因表达在人类早期,
男性和女性的大脑发育模式不同,这种模式构成了
男性和女性对神经发育障碍的不同易感性。我们设想
这些性别差异是由表观遗传程序控制的,
以性别偏见的方式调节基因的发育。我们进一步假设这些性-
依赖性表观遗传机制与影响风险的遗传风险因素相互作用,
自闭症谱系障碍(ASD)和精神分裂症(SCZ)的进展和严重程度,我们
将在两个具体目标中检验这些假设。目的1是阐明性别依赖性调节
典型个体的早期大脑发育。表观遗传学和基因表达程序
脑类器官和死后胎脑将在多个层面上进行评估,包括
转录组、蛋白质组和非编码调控元件的活性。这一目标的目的是
是定义一个基因及其调控元件的网络,主要是增强子,
在大脑发育早期,男性和女性的大脑活动有差异。目标2将
确定有性别偏见的监管网络是否增加了潜在的负担
致病性或风险相关的遗传变异的发育障碍,如SCZ和ASD。
我们将查询先证者和典型对照的可用基因组测序和GWAS数据集
以确定是否性别偏见的调节网络是丰富的罕见和常见的
遗传性疾病变异在性别偏见的调控网络中丰富这些变异将
揭示性别偏见基因表达影响SCZ和ASD遗传的潜在机制
风险和轨迹。这项工作的影响是寻求第一个详细了解早期
大脑发育的性别二态性新的知识将构成一个根本性的进步
在我们对正常发育的理解中,
易感性取决于发育中的大脑中性别偏向的基因调控。
项目成果
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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:
10610415 - 财政年份:2022
- 资助金额:
$ 94.01万 - 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:
$ 94.01万 - 项目类别:
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