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确定了数百种编码变体，这些变体增加了风险主要的神经精神疾病，这种自闭症谱系障碍。阐明非 - 的贡献编码变体也正在进行中，预计未来几年将迅速加速。而这些进步已大大提高了我们对遗传景观神经精神病学的理解疾病，对分子病理生理学的更深入了解仍缺失。这些知识差距应得在某种程度上，涉及风险基因座的异质性，它们在调节大型表达中的潜在作用基因数量，风险基因的多效性质以及神经精神疾病的可能性很高涉及多种细胞类型和大脑区域的功能失调的电路产生，完全使鉴定有问题的疾病的分子和细胞机制，尤其是在大脑发育的持久性和复杂性的背景。因此，发现和在人脑中活跃的功能基因组元素的全频谱的表征，它们跨时空维度的活性/表达模式对于阐明何时至关重要在哪里以及哪种细胞类型与神经精神疾病的病因和治疗有关。这是尤其是在不难以注释的非编码变体的背景下，却可能持有提供高度特定的空间，时间和细胞类型特定信息的承诺。解决这个问题知识差距并继续我们对Psychencode财团的贡献，我们提出了四个确定人神经发育的基因调节和细胞类型特异性机制的具体目的。在 AIM 1，我们确定单细胞（核），细胞类型，区域和区域的功能基因组元素神经型人类和猕猴后大脑的发育时间点。在AIM 2中，我们映射神经型人类和猕猴后大脑的时空蛋白质组。在AIM 3中，我们执行疾病大脑和IPSC衍生的功能基因组元素和蛋白质组学的综合鉴定神经细胞。在AIM 4中，我们将AIMS 1-3的结果以及与独立的遗传数据集相结合神经精神病种群，以识别将导致的非编码元素，基因或分子途径更好地理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。该提案的数据将也是社区成员的关键新资源，他们可以与之相交结果并得出更深入，更有意义的结论，尤其是从中的大量基因组数据神经精神疾病继续积累。