2/2 - Cell Type and Region-Specific Regulatory Networks in Human Brain Development and Disorders
2/2 - 人脑发育和疾病中的细胞类型和区域特异性调节网络
基本信息
- 批准号:10430082
- 负责人:
- 金额:$ 45.19万
- 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:2018-08-15 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:7q11.23ATAC-seqAddressAgeArchivesAutopsyBiological ModelsBrainBrain DiseasesBrain regionCell NucleusCell physiologyCellsChromatin Remodeling FactorCodeCollectionCommunitiesComplexCoupledDataData SetDevelopmentDiagnosisDimensionsDiseaseElementsEtiologyFluorescenceFreezingFunctional disorderGenesGeneticGenetic TranscriptionGenomicsHeterogeneityHumanJointsKnowledgeLinkMacacaMapsModalityMolecularMolecular ProfilingNatureNeuronsPathway interactionsPatientsPatternPopulationPost-Transcriptional RegulationProtein AnalysisProtein IsoformsProteomeProteomicsRegulator GenesRegulatory ElementResourcesRiskRoleSamplingSorting - Cell MovementSurveysSyndromeTimeTissuesTransgenic MiceUntranslated RNAValidationVariantWorkautism spectrum disorderbasecandidate selectioncell typeexperimental studyfunctional genomicsgenetic architecturegenetic regulatory proteingenomic dataimprovedinduced pluripotent stem cellinsightmembermouse modelneurodevelopmentneurogenomicsneuropsychiatric disorderneuropsychiatrynovelpostnatal developmentpostnatal humanprenatalrisk variantsample archivesingle-cell RNA sequencingspatiotemporaltranscription factortranscriptome sequencing
项目摘要
ABSTRACT
Recent advances in genetics and genomics have identified hundreds of coding variants that increase risk for
major neuropsychiatric disorders, such autism spectrum disorder. Work to clarify the contribution of non-
coding variants is also underway and is expected to accelerate rapidly in the next few years. While these
advances have considerably improved our understanding of the genetic landscape neuropsychiatric
disorders, a deeper understanding of molecular pathophysiology is still missing. This knowledge gap is due
to, in part, the heterogeneity of risk loci involved, their potential roles in regulating expression of a large
number of genes, the pleiotropic nature of risk genes, and the high likelihood that neuropsychiatric disorders
result from dysfunctional circuitry involving multiple cell types and brain regions, altogether making the
identification of molecular and cellular mechanisms underlying a disease problematic, especially in the
context of the protractive and complex nature of brain development. Therefore, the discovery and
characterization of the full spectrum of functional genomic elements active in the human brain, as well as
their activity/expression patterns across the spatiotemporal dimensions, is essential for clarifying when,
where, and what cell types are relevant to the etiology and treatment of neuropsychiatric disorders. This is
particularly so in the context of non-coding variants, which are difficult to annotate, yet potentially hold the
promise of providing highly specific spatial, temporal, and cell type specific information. To address this
knowledge gap and to continue our contributions to the PsychENCODE Consortium, we propose four
specific aims that identify gene regulatory and cell type-specific mechanisms of human neurodevelopment. In
Aim 1, we identify functional genomic elements across single cells (nuclei), cell types, regions and
developmental time points of neurotypical human and macaque postmortem brains. In Aim 2, we map the
spatio-temporal proteome of neurotypical human and macaque postmortem brains. In Aim 3, we perform
integrative identification of functional genomic elements and proteomics in diseased brains and iPSC-derived
neural cells. In Aim 4, we integrate results from Aims 1-3, as well as with independent genetic datasets of
neuropsychiatric populations, to identify non-coding elements, genes, or molecular pathways that will lead to
a better understanding of the underlying pathophysiological mechanisms of neuropsychiatric disorders.
Finally, these mechanisms will be functionally characterized in model systems. Data from this proposal will
also serve as a critical new resource for members of the community, with which they can intersect their
results and draw deeper and more meaningful conclusions, especially as the wealth of genomic data from
neuropsychiatric disorders continues to accumulate.
摘要
项目成果
期刊论文数量(0)
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{{ truncateString('MATTHEW W. STATE', 18)}}的其他基金
2/2 - Cell Type and Region-Specific Regulatory Networks in Human Brain Development and Disorders
2/2 - 人脑发育和疾病中的细胞类型和区域特异性调节网络
- 批准号:
9977706 - 财政年份:2018
- 资助金额:
$ 45.19万 - 项目类别:
2/7-Collaborative genomic studies of Tourette Disorder
2/7-抽动秽语症的合作基因组研究
- 批准号:
9975897 - 财政年份:2018
- 资助金额:
$ 45.19万 - 项目类别:
2/7-Collaborative genomic studies of Tourette Disorder
2/7-抽动秽语症的合作基因组研究
- 批准号:
10152673 - 财政年份:2018
- 资助金额:
$ 45.19万 - 项目类别:
2/2 - Cell Type and Region-Specific Regulatory Networks in Human Brain Development and Disorders
2/2 - 人脑发育和疾病中的细胞类型和区域特异性调节网络
- 批准号:
9764487 - 财政年份:2018
- 资助金额:
$ 45.19万 - 项目类别:
2/7-Collaborative genomic studies of Tourette Disorder
2/7-抽动秽语症的合作基因组研究
- 批准号:
10397559 - 财政年份:2018
- 资助金额:
$ 45.19万 - 项目类别:
2/7-Collaborative genomic studies of Tourette Disorder
2/7-抽动秽语症的合作基因组研究
- 批准号:
10598414 - 财政年份:2018
- 资助金额:
$ 45.19万 - 项目类别:
2/2 - Cell Type and Region-Specific Regulatory Networks in Human Brain Development and Disorders
2/2 - 人脑发育和疾病中的细胞类型和区域特异性调节网络
- 批准号:
10199973 - 财政年份:2018
- 资助金额:
$ 45.19万 - 项目类别:
2/7-Collaborative genomic studies of Tourette Disorder
2/7-抽动秽语症的合作基因组研究
- 批准号:
9751973 - 财政年份:2018
- 资助金额:
$ 45.19万 - 项目类别:
3/3 Integrative Genomic Analysis of Human Brain Development and Autism
3/3 人脑发育和自闭症的综合基因组分析
- 批准号:
9174866 - 财政年份:2016
- 资助金额:
$ 45.19万 - 项目类别:
2/3-Identifying regulatory mutations that influence neuropsychiatric disease
2/3-识别影响神经精神疾病的调节突变
- 批准号:
9282488 - 财政年份:2014
- 资助金额:
$ 45.19万 - 项目类别:
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