Molecular and anatomical characterization of cell types in the aging mouse brain

衰老小鼠大脑细胞类型的分子和解剖学特征

• 批准号: 10264014
• 负责人: Bosiljka Tasic
• 金额: $ 117.5万
• 依托单位: ALLEN INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10264014
• 关键词: Adult; Affect; Age; Aging; Alzheimer' s Disease; Anatomy; Area; Astrocytes; Atlases; BRAIN initiative; Behavioral; Blood Vessels; Brain; Brain Diseases; Brain region; Cataloging; Catalogs; Cell Nucleus; Cell physiology; Cells; Cellular Morphology; Censuses; Chromatin; Chromium; Classification; Collection; Data; Data Set; Databases; Disease; Female; Foundations; Gene Expression; Generations; Genes; Genetic Transcription; Grant; Image; Immune; Impaired cognition; Institutes; Maps; Measurement; Microglia; Molecular; Morphology; Mus; Neurodegenerative Disorders; Neuroglia; Neurons; Parkinson Disease; Participant; Pathology; Pathway interactions; Process; Reporting; Research; Resolution; Risk Factors; Sampling; Spatial Distribution; Surveys; Therapeutic; Time; age effect; age related; age related neurodegeneration; aging brain; base; brain cell; cell type; design; epigenomics; high dimensionality; insight; male; normal aging; reconstruction; single cell technology; single-cell RNA sequencing; stem cells; tomography; transcriptome sequencing; transcriptomics; young adult

Project Summary One of the most fundamental questions in brain aging research is whether age-related alterations affect all brain regions equally, or whether some regions, and cell types within those regions, are more vulnerable to the effects of aging than others. Aging is associated with cognitive decline, and is reported to cause alterations in a variety of important cellular processes and in a variety of cell types (e.g., microglia, astrocytes, neurons). Broad classes of cells in affected brain regions are known to be selectively vulnerable to age-related neurodegenerative diseases, but the specific molecular mechanisms underlying this vulnerability are unclear. An essential prerequisite to understanding this selective vulnerability is to understand the detailed changes at cell type and circuit levels during the aging process. Cataloging brain cell types and their connectivity in normal aging brain is foundational to uncovering the mechanisms and therapeutic opportunities for age-related brain disorders. State-of-the-art single-cell technologies, in particular single-cell transcriptomics with its high dimensional molecular information, but also spatial transcriptomics, single-cell epigenomics and single-cell morphology, are providing transformative information about brain cell types at an unprecedented scale and resolution. We propose to utilize our well-established omics pipelines to characterize and classify cell types in 18 months old male and female C57BL/6J mice and compare the results with the extensive brain-wide datasets in young adult (~P56) mice already being generated in the current BRAIN Initiative Cell Census Network (BICCN). We will use single-nucleus transcriptomics and epigenomics to obtain a high-level survey of neuronal and non-neuronal cell classes/types across the entire mouse brain, and then an in-depth single-cell and spatial transcriptomic study in brain areas showing age-related changes and/or vulnerable to neurodegenerative diseases. We will utilize our imaging–based registration process to map all data into the Common Coordinate Framework (CCF), which allows accurate cross-age quantitative comparisons that will be crucial for uncovering age-related changes. By conducting concurrent single-cell gene expression and chromatin accessibility measurements in the same brain regions, and a detailed spatial transcriptomic map of the proportion and distribution of different cell types and specific molecular pathways, we will chart an integrated path towards gaining mechanistic insight underlying the cognitive decline in aging and age-related disease pathology.

项目概要 大脑衰老研究中最基本的问题之一是与年龄相关的变化是否会影响所有大脑 区域同样如此，或者某些区域以及这些区域内的细胞类型是否更容易受到影响 比其他人更容易衰老。衰老与认知能力下降有关，据报道会导致多种方面的改变 重要的细胞过程和多种细胞类型（例如小胶质细胞、星形胶质细胞、神经元）。广泛的课程 已知受影响大脑区域的细胞选择性地容易受到与年龄相关的神经退行性疾病的影响 疾病，但这种脆弱性背后的具体分子机制尚不清楚。必不可少的 了解这种选择性脆弱性的先决条件是了解细胞类型和细胞类型的详细变化 老化过程中的电路电平。对正常老化大脑中的脑细胞类型及其连接进行编目是 为揭示与年龄相关的大脑疾病的机制和治疗机会奠定了基础。 最先进的单细胞技术，特别是具有高维度的单细胞转录组学 分子信息，还有空间转录组学、单细胞表观基因组学和单细胞形态学， 以前所未有的规模和分辨率提供有关脑细胞类型的变革性信息。我们 建议利用我们完善的组学流程对 18 个月大的细胞类型进行表征和分类 雄性和雌性 C57BL/6J 小鼠，并将结果与​​年轻成年小鼠的广泛全脑数据集进行比较 (~P56) 小鼠已在当前 BRAIN Initiative 细胞普查网络 (BICCN) 中生成。我们将使用 单核转录组学和表观基因组学以获得神经元和非神经元细胞的高水平调查 整个小鼠大脑的类别/类型，然后进行深入的单细胞和空间转录组学研究 大脑区域表现出与年龄相关的变化和/或易患神经退行性疾病。我们将利用我们的 基于成像的配准过程将所有数据映射到通用坐标框架（CCF）中，该框架 允许准确的跨年龄定量比较，这对于揭示与年龄相关的变化至关重要。经过 在同一大脑中同时进行单细胞基因表达和染色质可及性测量 区域，以及不同细胞类型和分布的比例和分布的详细空间转录组图 特定的分子途径，我们将绘制一条综合路径，以获得潜在的机制洞察 衰老和年龄相关疾病病理学中的认知能力下降。