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: 10615209
• 负责人: Bosiljka Tasic
• 金额: $ 114.89万
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615209
• 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; Gene Expression; Generations; Genes; Genetic Transcription; Grant; Image; Immune; Impaired cognition; 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; brain cell; cell type; design; epigenomics; high dimensionality; insight; male; normal aging; reconstruction; single cell technology; single nucleus RNA-sequencing; 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.

项目摘要 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影响所有大脑 区域平等，或这些区域内的某些区域和细胞类型是否更容易受到影响 衰老比其他人。衰老与认知能力下降有关，据报道会导致一种变化 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）。广泛的班级 已知受影响的大脑区域的细胞有选择地容易受到与年龄相关的神经退行性的影响 疾病，但是这种脆弱性的基本特定分子机制尚不清楚。必不可少的 理解这种选择性脆弱性的先决条件是了解细胞类型和 老化过程中的电路水平。分类脑细胞类型及其在正常衰老大脑中的连通性是 揭示与年龄相关的脑部疾病的机制和治疗机会的基础。 最先进的单细胞技术，特别是单细胞转录组学具有高维度 分子信息，以及空间转录组学，单细胞表观基因组学和单细胞形态是 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 提议利用我们公认的Omics管道来表征和分类18个月大的细胞类型 雄性和女性C57BL/6J小鼠，并将结果与​​年轻人的大脑范围数据集进行比较 （〜p56）已经在当前大脑启动细胞普查网络（BICCN）中生成的小鼠。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级调查 整个小鼠大脑的类/类型，然后进行深入的单细胞和空间转录组研究 大脑区域显示与年龄相关的变化和/或容易受到神经退行性疾病的影响。我们将利用我们的 基于成像的注册过程将所有数据映射到公共坐标框架（CCF）中， 允许准确的跨年龄定量比较，这对于发现与年龄相关的变化至关重要。经过 在同一大脑中进行并发的单细胞基因表达和染色质可及性测量 区域，以及不同细胞类型的比例和分布的详细空间转录图和 特定的分子途径，我们将绘制一条综合的路径，以获得基础的机械洞察力 衰老和与年龄有关的疾病病理学的认知能力下降。