A regulome and transcriptome atlas of fetal and adult human neurogenesis

胎儿和成人神经发生的调节组和转录组图谱

• 批准号: 10377713
• 负责人: Long Cai
• 金额: $ 554.85万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2024-09-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10377713
• 关键词: Address; Adult; Alzheimer' s Disease; Anatomy; Atlases; BRAIN initiative; Binding; Biology; Brain; Brain Diseases; Cell Count; Cell Lineage; Cell Nucleus; Cells; Censuses; Chromatin; Communities; Complement; Complex; DNA; Data; Defect; Development; Developmental Gene; Disease; Elements; Embryo; Embryonic Development; Epigenetic Process; Epitopes; Etiology; Evolution; Gene Expression; Genes; Genetic Transcription; Goals; Hippocampus (Brain); Human; Image; Investigation; Link; Location; Mammals; Maps; Mental Depression; Methods; Modeling; Mus; Names; Neuroglia; Neurons; Nuclear; Outcome Study; Pattern; Plant Roots; Population; Pregnancy; Process; Proliferating; Radial; Recording of previous events; Regulator Genes; Reporting; Research; Resolution; Resources; Role; Schizophrenia; Small Nuclear RNA; Spatial Distribution; Technology; Tissues; Transcript; adult neurogenesis; base; cell type; comparative; computing resources; cost; dentate gyrus; epigenome; fetal; genome-wide; granule cell; human data; indexing; innovation; multimodality; nerve stem cell; neurodevelopment; neurogenesis; neuropsychiatry; nonhuman primate; novel; novel therapeutics; postnatal; programs; spatiotemporal; stem cells; tool; transcription factor; transcriptome; transcriptomics

PROJECT SUMMARY Dynamic changes in the spatiotemporal patterning of transcription factor binding on cis-regulatory DNA elements drives the developmental transition of cell lineages during neurogenesis. In the human brain, neurons are generated from early embryonic development until early postnatal stages. The main neurogenic region in the adult brain is the dentate gyrus in the hippocampus. While adult hippocampal neurogenesis has been confirmed in the majority of mammals, it is unclear if this phenomenon exists in the human brain. Multiple neuropsychiatric conditions, including depression, schizophrenia and Alzheimer's disease are rooted in hippocampal defects. Despite role Therefore, the obvious importance of on and its in neurogenesis, our understanding of the cell diversity and tissue organization is highly incomplete. a dentate gyrus neuropsychiatric conditions, more complete cell census of the dentate gyrus across lifetime will increase our understanding of the mechanisms underlying fetal, early postnatal and adult neurogenesis, which could have a key role in the etiology of disease in humans. tools chromatin gyrus world computational resources The overarching goal of our proposal is to optimize and accelerate the use of scalable technologies and to perform unbiased, multimodal single-nucleus omics-based assessment of gene expression and accessibility combined with spatial transcriptomics profiling on tissue sections of human across stages. In this study, we bring together an interdisciplinary team of experts anatomy, spatial transcriptomics, neurodevelopment and biology to create a cell census of the dentate gyrus that will be integrated with existing from the BRAIN Initiative Cell Census Network and will be made freely available to the scientific dentate fetal, early postnatal and adult in single cell omics, human community. analyses early embryonic hippocampal and This Utilizing this large resource of omics data from the human dentate gyrus, we will perform the following three that aim to: (1) identify the cell diversity and tissue organization of human dentate gyrus across fetal, postnatal and adult stages; (2) uncover shared and distinct gene regulatory networks associated with and adult human hippocampal neurogenesis; and (3) study the evolution conservation of neurogenesis by performing comparative analysis with mouse and non-human primate single-cell spatial transcriptomic data that are readily accessible through the BRAIN Initiative Cell Census Network. innovative research program will, if successful,provide scalable technologies for multimodal and spatial omics profiling and a developmental and adult cell atlas of cell type diversity in the dentate gyrus , which will serve as a blueprint for studies of human hippocampal neurogenesis, selective vulnerability of cell types in disease, and the features of brain evolution that differentiates humans from other species.

项目摘要 转录因子在顺式调节DNA上结合的时空模式的动态变化 元素驱动神经发生过程中细胞谱系的发育过渡。在人脑中，神经元 从早期胚胎发育到产后早期产生。主要神经源区域 成年大脑是海马中的齿状回。成年海马神经发生已经 在大多数哺乳动物中得到证实，目前尚不清楚这种现象是否存在于人脑中。多种的 神经精神疾病，包括抑郁症，精神分裂症和阿尔茨海默氏病 海马缺陷。尽管 角色 所以， ON及其它的显而易见的重要性 在神经发生中，我们对细胞多样性和组织组织的理解高度不完整。 一个 齿状回神经精神疾病， 在整个生命周期中，齿状回的更完整的细胞普查将增加我们对 胎儿，早期产后和成人神经发生的机制，可能在 人类疾病的病因。 工具 染色质 回 世界 计算 资源 我们建议的总体目标是优化和加速使用可扩展技术和 执行基于基因表达和基于多模式的单核单核评估和 可访问性结合了人类组织部分的空间转录组学分析 跨阶段。在这项研究中，我们将一个跨学科团队组成 专家解剖学，空间转录组学，神经发育和 生物学创建将与现有的齿状回的细胞普查 从大脑启动细胞普查网络中，将自由地提供给科学的 齿状 胎儿，早期和成人 在单细胞磁体中，人类 社区。 分析 早期的 胚胎 海马 和 这 利用人类齿状回的大量OMIC数据资源，我们将执行以下三个 目的是：（1）确定人类齿状回的细胞多样性和组织组织， 产后和成人阶段； （2）发现与 和成年人类海马神经发生； （3）研究的进化保护 通过对小鼠和非人类灵长类动物单细胞进行比较分析来进行神经发生 通过大脑启动细胞普查网络易于访问的空间转录数据。 创新的研究计划将为多模式和空间提供可扩展技术 齿状细胞类型多样性的OMICS分析以及开发和成人细胞图集 回 ，哪个会 作为研究人类海马神经发生的蓝图，细胞类型的选择性脆弱性 疾病以及将人类与其他物种区分开的脑进化特征。