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Functionally guided adult whole brain cell atlas in human and NHP

人类和 NHP 的功能引导成人全脑细胞图谱

基本信息

批准号：
10523848
负责人：
Ed Lein
金额：
$ 2286.45万
依托单位：
ALLEN INSTITUTE
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：
2022-08-22 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10523848
关键词：
ATAC-seq Acute Adult Anatomy Animal Model Architecture Atlases Automobile Driving Basic Science Behavior Behavioral Biological Assay Biomedical Research Brain Brain Diseases Brain region Callithrix Cell Nucleus Cell physiology Cells Characteristics Classification Clinical Communities Complex Consensus Consent Coupled Data Data Analyses Development Didelphidae Disease Enhancers Ensure Foundations Freezing Functional Imaging Functional Magnetic Resonance Imaging Genes Genetic Genomics Goals Hippocampus (Brain)Histologic Human Image Individual Knowledge Label Link Macaca Magnetic Resonance Imaging Mammals Maps Measures Methods Modeling Molecular Molecular Analysis Molecular Profiling Monkeys Moods Morphology Mus Nerve Tissue Neurons Neurosciences Ontology Organism Outcome Pan Genus Pattern Perception Phenotype Population Primates Property Reference Standards Regulator Genes Research Resected Resources Rodent Salvelinus Sampling Slice Specimen Structure Subcellular Anatomy Taxonomy Techniques Technology Tissues Variant Visualization software Work base brain cell brain circuitry brain tissue cell type cohort comparative computerized data processing data integration data management data mining data resource data standards data visualization electrical property end of life epigenomics human disease human model human subject human tissue in vivo in vivo imaging inter-individual variation member multimodality nervous system disorder neuroethics neuroimaging nonhuman primate patch sequencing sex single cell technology study population tool transcriptome transcriptome sequencing transcriptomics

项目摘要

Progress in treating brain disorders has been frustratingly slow, in large part due to the extraordinary complexity of the human brain and its inaccessibility to study. Remarkable advances in technologies for studying individual cells, most notably single cell genomics, have revolutionized the study of complex nervous tissues and have been used to map cellular diversity across the entire mouse brain with cell types defined by their specific patterns of gene usage and gene regulatory mechanisms. These highly scalable methods have been successfully applied to brain tissue from human and other species and are ready to be applied to whole brains from humans and non-human primates. A major challenge with studying the human brain is bridging fields and scales from functional MRI and macroscale connectomics to histological, cellular and molecular analyses. Bridging these domains is essential to creating a transformative new cell atlas that will describe the cellular and molecular underpinnings of the functional organization of the human brain. An important recent development from single cell genomic analysis is that cell types can be aligned across species and are highly conserved across mammals from mice to humans, although more similar in evolutionarily closer primates than in rodents. This finding amplifies the value of primate species in helping to understand human brains and infer cellular properties that cannot be measured in humans. The current proposal brings together a unique team of world leaders to tackle the challenge of creating a new human and non-human primate cell atlas linked to functional brain architecture. Single cell transcriptomic, epigenomic and spatial transcriptomics will be used to classify and spatially map cell types across the entire human, macaque and marmoset brain, sampling based on brain maps derived from structural and functional imaging. Function-localizing fMRI in macaques will allow the direct analysis of cellular correlates of functional topography. Advances in spatial transcriptomics will allow an unprecedented whole primate brain map of cell types. Unique access to macaque tissues for analysis of cellular anatomy and physiology allows the characterization of molecularly-defined cell types in many brain regions. Similar techniques will be applied to living neurosurgically-derived human brain tissues, coupled with enhancer-AAV based tools to allow selective genetic labeling of cell types. Finally, profiling regions central to perception, behavior and mood across many individuals and diverse mammals will link genetic, environmental and evolutionary factors to cellular variation. The outcome of these efforts will produce a new reference classification for cell types across the whole human and NHP brain, spatial maps of molecularly defined cell types, and phenotypic characterization of fundamental brain cell types. The classification will align homologous cell types from mice, marmosets, macaques and humans, allowing inference and comparison of cellular properties across species. Furthermore, data will be aligned in common coordinate frameworks, allowing creation of new atlases spanning structural, functional, cellular and molecular information. All data and analyses will be distributed to the research community, including a formal cell ontology of cell types across species and visualization tools for broad community access.

治疗脑部疾病的进展缓慢得令人沮丧，这在很大程度上是由于脑部疾病的异常复杂性人脑及其难以研究。研究单个细胞的技术取得了显着进步，大多数尤其是单细胞基因组学，彻底改变了复杂神经组织的研究，并已被用于绘制细胞图谱整个小鼠大脑的多样性，其细胞类型由其特定的基因使用和基因调控模式定义机制。这些高度可扩展的方法已成功应用于人类和其他物种的脑组织并准备好应用于人类和非人类灵长类动物的整个大脑。研究的一个重大挑战人类大脑正在连接从功能性 MRI 和宏观连接组学到组织学、细胞学和分子分析。连接这些领域对于创建一个变革性的新细胞图谱至关重要，该图谱将描述人脑功能组织的细胞和分子基础。最近一个重要的单细胞基因组分析的发展是细胞类型可以跨物种比对并且高度保守从老鼠到人类的哺乳动物中都有这种现象，尽管在进化上更接近的灵长类动物比啮齿类动物更相似。这一发现放大了灵长类动物在帮助理解人类大脑和推断细胞特性方面的价值在人类中测量。当前的提案汇集了一个由世界领导人组成的独特团队，以应对创造新人类和新人类的挑战。与功能性大脑结构相关的非人类灵长类细胞图谱。单细胞转录组、表观基因组和空间转录组学将用于对整个人类、猕猴和狨猴的细胞类型进行分类和空间绘图大脑，根据结构和功能成像得出的大脑图进行采样。猕猴功能定位功能磁共振成像将允许直接分析功能拓扑的细胞相关性。空间转录组学的进步将允许前所未有的灵长类动物全脑细胞类型图。独特地获取猕猴组织以进行细胞分析解剖学和生理学允许对许多大脑区域中分子定义的细胞类型进行表征。相似的技术将应用于活体神经外科衍生的人脑组织，并结合基于增强子 AAV 的工具允许对细胞类型进行选择性基因标记。最后，对感知、行为和情绪的核心区域进行分析许多个体和不同的哺乳动物会将遗传、环境和进化因素与细胞变异联系起来。这些努力的成果将为整个人类和 NHP 的细胞类型提供新的参考分类大脑、分子定义的细胞类型的空间图以及基本脑细胞类型的表型特征。这分类将比对来自小鼠、狨猴、猕猴和人类的同源细胞类型，从而可以进行推断和跨物种细胞特性的比较。此外，数据将在通用坐标框架中对齐，允许创建涵盖结构、功能、细胞和分子信息的新图谱。所有数据和分析将分发给研究界，包括跨物种细胞类型的正式细胞本体论和可视化用于广泛社区访问的工具。