A Multidisciplinary Center for Developing Human and Non-human Primate Brain Cell Atlases

开发人类和非人类灵长类动物脑细胞图谱的多学科中心

基本信息

批准号：
10705743
负责人：
Aparna Bhaduri
金额：
$ 332.64万
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：
2022
资助国家：
美国
起止时间：
2022-09-16 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10705743
关键词：
3-Dimensional ATAC-seq Adolescence Adult Age Anatomy Atlases Brain Brain region Callithrix Callithrix jacchus jacchus Cell Lineage Cell Nucleus Cells Cellular Assay Censuses Childhood Chromatin Communities Complex Computer Analysis Country Data Data Analyses Data Set Development Disease Epigenetic Process Etiology Evolution Freezing Gene Expression Generations Genes Genomics Goals Health Human Institution Laboratories Longevity Macaca Macaca mulatta Magnetic Resonance Imaging Maps Modality Molecular Monitor Neonatal Neuroanatomy Neurodevelopmental Disorder Pattern Population Positioning Attribute Pregnancy Primates Procedures Property Protocols documentation RNA Regulator Genes Regulatory Element Research Resolution Resources Sampling Schizophrenia Series Spatial Distribution Specimen Taxonomy Technology Transposase Validation Visualization autism spectrum disorder brain cell brain tissue cell type comparative data framework data integration differential expression epigenome epigenomics genetic signature human disease human model human tissue improved in vitro Model innovation insight multidisciplinary multiple omics neuropsychiatric disorder nonhuman primate primate development single nucleus RNA-sequencing transcriptome sequencing transcriptomics

项目摘要

Project Summary The ultimate product of our Center will be a series of comprehensive developing human and non-human primate (NHP) brain atlases of unprecedented cellular, spatial, and anatomical resolution. In Aim 1, we will characterize transient cell populations, establish the diversity of cell types present in specific brain regions, unravel complex developmental trajectories, and reveal conserved and divergent cell-type specific features. We will jointly profile of single nucleus RNA (snRNA-seq) and accessible chromatin (snATAC-seq) using the 10X Genomics snMultiome platform. All aims will include 30 anatomically distinct regions of fresh frozen developing human, rhesus macaque, and marmoset brains at four developmental epochs: mid-gestation, neonatal, childhood, and adolescence and perform probe-based validation. In Aim 2, we will conduct spatial transcriptomic and epigenomic mapping of cell types in fresh-frozen developing human and NHP brains using DBiT spatial-RNA-seq and spatial-ATAC-seq platforms. This approach will allow us to discover spatial and temporal features, including the developmental niche, proximity of cell types to each other, and regional abundance. In Aim 3 we will create Common Coordinate Frameworks for the developing human and NHP brain using high resolution (9.4T and 7T) MRI-based developmental structural atlases and leveraging existing developing human MRI data. Our final aim will create a cross species molecular and spatial atlas of brain development in human and NHP. This integration will enable us to identify conserved and diveregent aspects of the human brain and identify the developmental stages, spatial distribution, gene regulatory elements and cell types vulnerable to neurodevelopmental and neuropsychiatric disorders. We will coordinate to ensure that our developmental atlases merge with adult human, macaque and marmoset atlases that other BICAN centers create. The data collected by our Center will be perfectly aligned with the overarching goal of the BICCN in generating a comprehensive census of brain cell types across the lifespan that integrates molecular, anatomical, functional, and cell lineage data for describing cell types in human and NHP brains. By leveraging innovations in cell capture and spatial mapping technologies, the current proposal will have broad implications for understanding the cellular origins of diseases and for highlighting patterns of selective cell type vulnerability in neurodevelopmental disorders such as autism and schizophrenia. Additionally, our plans to create developmental cellular and molecular resolution maps of marmoset and macaque will provide foundational data for establishing primate models of human disease. Finally, our atlas of conserved molecular, epigenetic, and spatial properties will support the precise monitoring, targeting, and replacement of specific cell types and the improvement of in vitro models.

项目概要我们中心的最终产品将是一系列全面发育的人类和非人灵长类动物 (NHP) 具有前所未有的细胞、空间和解剖分辨率的脑图谱。在目标 1 中，我们将描述瞬时细胞群，建立特定大脑区域中存在的细胞类型的多样性，解开复杂的问题发育轨迹，并揭示保守和不同的细胞类型特定特征。我们将共同简介使用 10X Genomics 分析单核 RNA (snRNA-seq) 和可及染色质 (snATAC-seq) snMultiome 平台。所有目标将包括新鲜冷冻发育中的人类 30 个解剖学上不同的区域，恒河猴和狨猴的大脑在四个发育阶段：妊娠中期、新生儿、儿童和青春期并执行基于探针的验证。在目标 2 中，我们将对新鲜冷冻的细胞类型进行空间转录组和表观基因组作图。使用 DBiT 空间 RNA 序列和空间 ATAC 序列平台开发人类和 NHP 大脑。这种做法将使我们能够发现空间和时间特征，包括发育生态位、细胞类型的邻近性相互之间以及区域丰富性。在目标 3 中，我们将为使用基于高分辨率（9.4T 和 7T）MRI 的发育结构来发育人类和 NHP 大脑地图集并利用现有的开发人类 MRI 数据。我们的最终目标是创造一种跨物种分子人类和 NHP 大脑发育的空间图谱。这种整合将使我们能够识别保守的和人脑的不同方面，并确定发育阶段、空间分布、基因易受神经发育和神经精神疾病影响的调节元件和细胞类型。我们将协调以确保我们的发育图集与成年人、猕猴和狨猴图集融合其他 BICAN 中心创建的。我们中心收集的数据将与 BICCN 的总体目标完全一致对整个生命周期的脑细胞类型进行全面普查，整合了分子、解剖学、用于描述人类和 NHP 大脑中细胞类型的功能和细胞谱系数据。通过利用创新在细胞捕获和空间测绘技术方面，当前的提案将对了解疾病的细胞起源并强调选择性细胞类型脆弱性的模式神经发育障碍，例如自闭症和精神分裂症。此外，我们计划创建狨猴和猕猴的发育细胞和分子分辨率图将提供基础数据用于建立人类疾病的灵长类动物模型。最后，我们的保守分子、表观遗传和空间特性将支持特定细胞类型和细胞的精确监测、靶向和替换体外模型的改进。