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

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)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 瞬时细胞群体，建立存在于特定大脑区域的细胞类型的多样性，解开复合体 发育轨迹，并揭示保守的和发散的细胞型特定特征。我们将联合介绍 利用10X基因组学研究单核RNA(SnRNA-Seq)和可及染色质(SnATAC-Seq) SnMultiome平台。所有目标将包括30个解剖上不同的新鲜冷冻发育中人的区域， 恒河猴和恒河猴大脑在四个发育阶段：孕中期、新生儿、儿童期和 青春期，并执行基于探测器的验证。 在目标2中，我们将对新鲜冷冻的细胞类型进行空间转录和表观基因组图谱 利用DBiT SPATIAL-RNA-SEQ和SPATIAL-ATAC-SEQ平台开发人和NHP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、细胞类型的接近程度 彼此之间，以及地区的丰饶。在Aim 3中，我们将为 基于高分辨率(9.4T和7T)MRI的人脑和NHP脑发育结构研究 地图集和利用现有的发展中的人类核磁共振数据。我们的最终目标是创造一种跨物种的分子 以及人类和NHP大脑发育的空间图谱。这种集成将使我们能够识别保守的 以及人类大脑的不同方面，并确定发育阶段、空间分布、基因 易受神经发育和神经精神障碍影响的调节元件和细胞类型。我们会 协调确保我们的发育图集与成人、猕猴和绒猴图集相结合 其他比肯中心创造的。 我们中心收集的数据将与BICCN#年的总体目标完全一致 在整个生命周期内生成一个全面的脑细胞类型普查，将分子、解剖学、 用于描述人类和NHP大脑中的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，目前的提议将对以下方面产生广泛影响 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 恒河猴和猕猴的发育细胞和分子分辨率图谱将提供基础数据 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、表观遗传学和 空间属性将支持对特定单元类型和 体外模型的改进。

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.