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A platform for cell type-level transcriptomic, epigenomic and spatial interrogation of Alzheimer's disease

阿尔茨海默氏病细胞类型水平转录组、表观基因组和空间研究的平台

基本信息

批准号：
10612878
负责人：
Jennie Leigh Close
金额：
$ 955.55万
依托单位：
ALLEN INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10612878
关键词：
Adult Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Anatomy Architecture Autopsy BRAIN initiative Basic Science Biological Assay Brain Brain Mapping Cell Nucleus Cells Cellular Neurobiology Characteristics Clinical Collaborations Collection Communication Communities Complex Data Data Collection Data Set Deposition Disease Disease Resistance Epigenetic Process Future Generations Genetic Genetic Transcription Genomic approach Genomics Goals Health Histology Human Infrastructure Leadership Link Maps Methodology Methods Modality Modernization Molecular Molecular Neurobiology Molecular Profiling Neuroglia Neurons Organ Pathogenesis Pathologic Pathology Pathway interactions Phase Preparation Progress Reports Proteins RNA Research Research Personnel Resistance Resolution Science Severities Standardization Strategic Planning Techniques Technology Tissue Banks Tissues Universities Visualization Washington brain research brain tissue cell type clinical phenotype cohort computerized data processing data access data management data portal data resource design disorder subtype diverse data epigenome epigenomics human tissue improved insight member molecular pathology molecular scale neuropathology next generation organizational structure single cell analysis tissue resource tool transcriptome transcriptomics

项目摘要

ABSTRACT (OVERALL) Our understanding of the neuropathology in Alzheimer’s disease is crude and largely centered on characteristic deposition of a few pathological proteins. Catalyzed by the BRAIN Initiative, a new generation of molecular tools to characterize the transcriptome, epigenome and spatial organization of single cells in complex brain tissues is rapidly revolutionizing our understanding of the diversity of cell types and their selective genetic profiles. These tools are applicable to postmortem human brain tissues and promise to expand our understanding of the core cellular and molecular correlates and mechanisms underlying Alzheimer’s disease. The goal of the proposed Center is to bring together experts in Alzheimer’s disease research and large-scale molecular/anatomical brain mapping to modernize Alzheimer’s disease tissue banking methods, and to combine traditional and quantitative neuropathology with emerging single nucleus transcriptomics, single nucleus epigenomics and spatial transcriptomics technologies. Applied to clinically typical Alzheimer’s cases of varying severity in an iterative and adaptive design, these techniques are expected to identify increasingly refined molecular pathways associated with specific neuronal and non-neuronal cell types and yield valuable insights into cell-type selective vulnerability or resistance to pathology. This increased resolution of AD pathology in terms of cell types and molecular pathways should provide mechanistic insights and hypotheses on disease initiation and progression, which we aim to use to catalyze the AD research community through the creation of an open access data resource linked with other large-scale brain mapping efforts. This Center framework is designed to be extensible to additional data modalities and technological advances as well as broader cohorts representing Alzheimer’s disease subtypes and Alzheimer’s disease related disorders in the future.

摘要（总体）我们对阿尔茨海默病神经病理学的理解很粗略，并且主要集中在特征上一些病理蛋白的沉积。在 BRAIN Initiative 的催化下，新一代分子工具表征复杂脑组织中单细胞的转录组、表观基因组和空间组织是迅速彻底改变了我们对细胞类型多样性及其选择性遗传图谱的理解。这些工具适用于死后人类脑组织，有望扩大我们对核心的理解阿尔茨海默病的细胞和分子相关性和机制。拟议的目标该中心将汇集阿尔茨海默病研究和大规模分子/解剖大脑方面的专家绘制现代化阿尔茨海默病组织库方法，并将传统方法与定量方法相结合神经病理学与新兴的单核转录组学、单核表观基因组学和空间组学转录组学技术。应用于不同严重程度的临床典型阿尔茨海默病病例的迭代和通过适应性设计，这些技术有望识别出日益精细的相关分子途径具有特定的神经元和非神经元细胞类型，并对细胞类型选择性脆弱性产生有价值的见解或对病理的抵抗力。这提高了 AD 病理学在细胞类型和分子方面的分辨率。途径应提供有关疾病发生和进展的机制见解和假设，我们旨在通过创建链接的开放访问数据资源来促进AD研究社区与其他大规模脑图绘制工作一起。该中心框架旨在可扩展至其他数据模式和技术进步以及代表阿尔茨海默病的更广泛群体未来的亚型和阿尔茨海默病相关疾病。