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：
10199973
负责人：
MATTHEW W. STATE
金额：
$ 45.19万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
https://reporter.nih.gov/project-details/10199973
关键词：
7q11.23 ATAC-seq Address Age Archives Autopsy Biological Models Brain Brain Diseases Brain region Cell Nucleus Cell physiology Cells Chromatin Remodeling Factor Code Collection Communities Complex Coupled Data Data Set Development Diagnosis Dimensions Disease Elements Etiology Fluorescence Freezing Functional disorder Genes Genetic Genetic Transcription Genomics Heterogeneity Human Joints Knowledge Link Macaca Maps Modality Molecular Molecular Profiling Nature Neurons Pathway interactions Patients Pattern Population Post-Transcriptional Regulation Protein Analysis Protein Isoforms Proteome Proteomics Regulator Genes Regulatory Element Resources Risk Role Sampling Sorting - Cell Movement Surveys Syndrome Time Tissues Transgenic Mice Untranslated RNA Validation Variant Work autism spectrum disorder base candidate selection cell type experimental study functional genomics genetic architecture genetic regulatory protein genomic data improved induced pluripotent stem cell insight member mouse model neurodevelopment neurogenomics neuropsychiatric disorder neuropsychiatry novel postnatal development postnatal human prenatal risk variant sample archive single-cell RNA sequencing spatiotemporal transcription factor transcriptome 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.

抽象的遗传学和基因组学的最新进展已经发现了数百种编码变体，这些变体会增加患病风险主要的神经精神疾病，例如自闭症谱系障碍。努力澄清非编码变体也在进行中，预计在未来几年内会迅速加速。虽然这些进步大大提高了我们对神经精神遗传景观的理解疾病，仍然缺乏对分子病理生理学的更深入的了解。这种知识差距是由于部分原因是所涉及的风险位点的异质性，以及它们在调节大量基因表达中的潜在作用基因的数量、风险基因的多效性以及神经精神疾病的高可能性这是由于涉及多种细胞类型和大脑区域的电路功能失调造成的，这使得识别疾病问题背后的分子和细胞机制，特别是在大脑发育的长期性和复杂性的背景。因此，发现和人脑中活跃的全谱功能基因组元件的表征，以及他们在时空维度上的活动/表达模式对于澄清何时至关重要何处以及哪些细胞类型与神经精神疾病的病因学和治疗相关。这是特别是在非编码变体的情况下，这些变体很难注释，但可能保留承诺提供高度特定的空间、时间和细胞类型特定信息。为了解决这个问题为了继续为 PsychENCODE 联盟做出贡献，我们提出了四个建议确定人类神经发育的基因调控和细胞类型特异性机制的具体目标。在目标 1，我们鉴定跨单细胞（细胞核）、细胞类型、区域和神经典型人类和猕猴死后大脑的发育时间点。在目标 2 中，我们绘制了神经典型人类和猕猴死后大脑的时空蛋白质组。在目标 3 中，我们执行对患病大脑和 iPSC 衍生的功能基因组元件和蛋白质组学进行综合鉴定神经细胞。在目标 4 中，我们整合了目标 1-3 的结果以及独立的遗传数据集神经精神病学人群，以确定将导致的非编码元件、基因或分子途径更好地了解神经精神疾病的潜在病理生理机制。最后，这些机制将在模型系统中进行功能表征。该提案中的数据将也可以作为社区成员的重要新资源，他们可以通过这些资源交叉他们的结果并得出更深入、更有意义的结论，特别是随着基因组数据的丰富神经精神疾病继续累积。