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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大脑异常复杂