1/2 Cell Type and Region-Specific Regulatory Networks in Human Brain Development and Disorders
人脑发育和疾病中的 1/2 细胞类型和区域特异性调节网络
基本信息
- 批准号:10377340
- 负责人:
- 金额:$ 123.81万
- 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:2018-07-06 至 2024-03-31
- 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
遗传学和基因组学的最新进展已经确定了数百种编码变异,这些变异增加了
严重的神经精神障碍,如自闭症谱系障碍。努力澄清非编码的贡献
变体也在进行中,预计在未来几年内将迅速加速。虽然这些进步
大大提高了我们对遗传景观神经精神疾病的理解,更深层次的
对分子病理生理学的理解仍然缺失。这种知识差距部分是由于
风险基因座的异质性,它们在调节大量基因表达中的潜在作用,
风险基因的多效性,以及神经精神疾病由功能障碍引起的高可能性,
涉及多种细胞类型和大脑区域的电路,共同识别分子和
细胞机制潜在的疾病问题,特别是在长期和复杂的背景下,
大脑发育的本质因此,发现和表征全谱的功能
在人脑中活跃的基因组元件,以及它们在大脑中的活性/表达模式,
时空维度,对于澄清何时,何地以及哪些细胞类型与细胞相关至关重要。
神经精神疾病的病因学和治疗。在非编码环境中尤其如此
变体,这是难以注释,但潜在地持有提供高度具体的空间,
时间和细胞类型特定信息。为了弥补这一知识差距,继续我们的贡献,
对于PsychENCODE联盟,我们提出了四个确定基因调控和细胞类型的具体目标-
人类神经发育的特殊机制。在目标1中,我们确定了功能基因组元件,
人和猕猴神经典型的单个细胞(细胞核)、细胞类型、区域和发育时间点
死后的大脑目的二是对人和猕猴的神经元时空蛋白质组进行定位
死后的大脑在目标3中,我们进行功能基因组元件的整合鉴定,
蛋白质组学在患病的大脑和iPSC衍生的神经细胞中的应用。在目标4中,我们将目标1-3的结果整合为:
以及神经精神病人群的独立遗传数据集,以识别非编码元件,
基因,或分子途径,这将导致更好地了解潜在的病理生理
神经精神障碍的机制。最后,这些机制将在功能上的特点,
模型系统该提案中的数据也将成为联合国环境规划署成员的重要新资源。
社区,与他们可以交叉他们的结果,并得出更深入,更有意义的结论,
特别是随着来自神经精神疾病的基因组数据的财富不断积累。
项目成果
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The 7q11.23 Protein DNAJC30 Interacts with ATP Synthase and Links Mitochondria to Brain Development.
- DOI:10.1016/j.cell.2018.09.014
- 发表时间:2018-11-01
- 期刊:
- 影响因子:64.5
- 作者:Tebbenkamp ATN;Varela L;Choi J;Paredes MI;Giani AM;Song JE;Sestan-Pesa M;Franjic D;Sousa AMM;Liu ZW;Li M;Bichsel C;Koch M;Szigeti-Buck K;Liu F;Li Z;Kawasawa YI;Paspalas CD;Mineur YS;Prontera P;Merla G;Picciotto MR;Arnsten AFT;Horvath TL;Sestan N
- 通讯作者:Sestan N
LSD1 inhibition sustains T cell invigoration with a durable response to PD-1 blockade.
- DOI:10.1038/s41467-021-27179-7
- 发表时间:2021-11-24
- 期刊:
- 影响因子:16.6
- 作者:Liu Y;Debo B;Li M;Shi Z;Sheng W;Shi Y
- 通讯作者:Shi Y
Transcriptional priming as a conserved mechanism of lineage diversification in the developing mouse and human neocortex.
- DOI:10.1126/sciadv.abd2068
- 发表时间:2020-11
- 期刊:
- 影响因子:13.6
- 作者:Li Z;Tyler WA;Zeldich E;Santpere Baró G;Okamoto M;Gao T;Li M;Sestan N;Haydar TF
- 通讯作者:Haydar TF
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{{ truncateString('NENAD SESTAN', 18)}}的其他基金
Identification of Genetic and Molecular Bases of Derived Phenotypes in Primate Brain Development
灵长类动物大脑发育中衍生表型的遗传和分子基础的鉴定
- 批准号:
10841947 - 财政年份:2023
- 资助金额:
$ 123.81万 - 项目类别:
1/2 Identification and Validation of Expression Quantitative Trait Loci (eQTLs) in discrete cell types across human brain development
1/2 人脑发育过程中离散细胞类型表达数量性状位点 (eQTL) 的识别和验证
- 批准号:
9948364 - 财政年份:2021
- 资助金额:
$ 123.81万 - 项目类别:
1/2 Identification and Validation of Expression Quantitative Trait Loci (eQTLs) in discrete cell types across human brain development
1/2 人脑发育过程中离散细胞类型表达数量性状位点 (eQTL) 的识别和验证
- 批准号:
10335113 - 财政年份:2021
- 资助金额:
$ 123.81万 - 项目类别:
1/2 Identification and Validation of Expression Quantitative Trait Loci (eQTLs) in discrete cell types across human brain development
1/2 人脑发育过程中离散细胞类型表达数量性状位点 (eQTL) 的识别和验证
- 批准号:
10543826 - 财政年份:2021
- 资助金额:
$ 123.81万 - 项目类别:
Identification of Genetic and Molecular Bases of Derived Phenotypes in Primate Brain Development
灵长类动物大脑发育中衍生表型的遗传和分子基础的鉴定
- 批准号:
10437866 - 财政年份:2020
- 资助金额:
$ 123.81万 - 项目类别:
Developmental cell census of human and non-human primate brain
人类和非人类灵长类动物大脑的发育细胞普查
- 批准号:
10088878 - 财政年份:2020
- 资助金额:
$ 123.81万 - 项目类别:
Identification of Genetic and Molecular Bases of Derived Phenotypes in Primate Brain Development
灵长类动物大脑发育中衍生表型的遗传和分子基础的鉴定
- 批准号:
10256054 - 财政年份:2020
- 资助金额:
$ 123.81万 - 项目类别:
Developmental cell census of human and non-human primate brain
人类和非人类灵长类动物大脑的发育细胞普查
- 批准号:
10266105 - 财政年份:2020
- 资助金额:
$ 123.81万 - 项目类别:
Technology for functional study of cells and circuits in large postmortem brains ex vivo
离体大型死后大脑细胞和电路功能研究技术
- 批准号:
9928247 - 财政年份:2019
- 资助金额:
$ 123.81万 - 项目类别:
1/2 Cell Type and Region-Specific Regulatory Networks in Human Brain Development and Disorders
人脑发育和疾病中的 1/2 细胞类型和区域特异性调节网络
- 批准号:
9896867 - 财政年份:2018
- 资助金额:
$ 123.81万 - 项目类别:
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