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: 10523935
• 负责人: Aparna Bhaduri
• 金额: $ 732.78万
• 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/10523935
• 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; Ensure; Epigenetic Process; Etiology; Evolution; Foundations; 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; Resource Sharing; Resources; Sampling; Schizophrenia; Series; Small Nuclear RNA; Spatial Distribution; Specimen; Taxonomy; Technology; Transposase; Validation; Visualization; autism spectrum disorder; base; brain cell; brain tissue; cell type; comparative; data integration; differential expression; epigenome; epigenomics; genetic signature; human disease; human model; human tissue; in vitro Model; innovation; insight; multidisciplinary; neuropsychiatric disorder; nonhuman primate; primate development; 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类灵长类动物 （NHP）前所未有的细胞，空间和解剖分辨率的大脑图谱。在AIM 1中，我们将描述 瞬态细胞群体，建立特定大脑区域中存在的细胞类型的多样性，解开复合物 发育轨迹，并揭示了保守和不同的细胞类型特定特征。我们将共同概况 使用10X基因组学 Snmultiome平台。所有目标都将包括30个解剖学上不同的新鲜冷冻发展的人， 恒河猕猴和四个发育时期的Marmoset大脑：中期，新生儿，童年和 青春期并执行基于探针的验证。 在AIM 2中，我们将在新鲜冻结中进行细胞类型的空间转录组和表观基因组映射 使用DBIT空间-RNA-seq和空间-ATAC-SEQ平台来开发人和NHP大脑。这种方法 将允许我们发现空间和时间特征，包括发育生态位，细胞类型的邻近 彼此，区域丰富。在AIM 3中，我们将为 使用高分辨率（9.4T和7T）基于MRI的发育结构来开发人和NHP大脑 地图集并利用现有的开发人类MRI数据。我们的最终目标将创建一个跨物种分子 和人类和NHP中大脑发育的空间地图集。这种整合将使我们能够确定保守的 和人脑的分裂方面，并确定发育阶段，空间分布，基因 容易受到神经发育和神经精神疾病的调节元素和细胞类型。我们将 协调以确保我们的发展地图集与成年人，猕猴和摩尔摩斯群岛合并 那些比坎中心创造的。 我们中心收集的数据将与BICCN的总体目标完全一致 在整个生命周期中生成脑细胞类型的全面普查，该寿命整合了分子，解剖学， 用于描述人和NHP大脑中细胞类型的功能和细胞谱系数据。通过利用创新 在细胞捕获和空间映射技术中，当前的建议将对 了解疾病的细胞起源，并突出显示选择性细胞类型漏洞的模式 神经发育障碍，例如自闭症和精神分裂症。此外，我们创建的计划 Marmoset和猕猴的发育性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，我们保守的分子，表观遗传和 空间特性将支持特定细胞类型的精确监视，靶向和替换 改进体外模型。