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

• 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
• 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

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.

项目摘要 我们中心的最终产品将是一系列全面发展的人类和非人灵长类动物 (NHP)前所未有的细胞、空间和解剖分辨率的大脑图谱。在目标1中，我们将描述 短暂的细胞群，建立细胞类型的多样性存在于特定的大脑区域，解开复杂的 发展轨迹，并揭示保守和不同的细胞类型的具体特点。我们将共同描绘 单核RNA（snRNA-seq）和可接近染色质（snATAC-seq）的分析 snMultiome平台。所有目标将包括30个解剖学上不同的新鲜冷冻发育中的人类区域， 恒河猴和绒猴脑在四个发育时期：妊娠中期，新生儿，儿童， 青春期，并进行基于探测的验证。 在目标2中，我们将对新鲜冷冻细胞中的细胞类型进行空间转录组学和表观基因组学作图， 使用DBiT spatial-RNA-seq和spatial-ATAC-seq平台开发人脑和NHP脑。这种方法 将使我们能够发现空间和时间特征，包括发育生态位，细胞类型的接近性， 和地区性的富足。在目标3中，我们将为 使用基于高分辨率（9.4T和7 T）MRI的发育结构开发人类和NHP大脑 地图集和利用现有的开发中的人类MRI数据。我们的最终目标是创造一个跨物种的分子 以及人类和NHP脑发育的空间图谱。这种整合将使我们能够识别保守的 和人类大脑的不同方面，并确定发育阶段，空间分布，基因 调节元件和易受神经发育和神经精神障碍影响的细胞类型。我们将 协调以确保我们的发育图谱与成年人、猕猴和绒猴图谱相融合 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， 对整个生命周期内的脑细胞类型进行全面的普查，整合了分子、解剖、 功能和细胞谱系数据，用于描述人脑和NHP脑中的细胞类型。通过利用创新 在细胞捕获和空间映射技术方面，目前的提议将对以下方面产生广泛的影响： 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，如自闭症和精神分裂症。此外，我们计划创建 绒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，我们的保守分子图谱，表观遗传， 空间特性将支持特定细胞类型的精确监测、靶向和替换， 体外模型的改进。