Project 1: 3-D Molecular atlas of the aging brain

项目 1：衰老大脑的 3D 分子图谱

• 批准号: 10555897
• 负责人: Hemali Phatnani
• 金额: $ 59.49万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555897
• 关键词: 3-Dimensional; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyotrophic Lateral Sclerosis; Antibodies; Atlases; Autopsy; Behavioral; Blood Vessels; Brain region; Cerebrovascular Disorders; Chromosome Mapping; Clinical; Cognitive; Complement; Computer Models; Data; Data Set; Defect; Development; Disease; Dissociation; Elderly; Environment; Frontotemporal Dementia; Gene Expression; Gene Expression Profile; Generations; Genes; Genomics; Global Change; Goals; Human; Image; Immunohistochemistry; In Situ Hybridization; Indirect Immunofluorescence; Individual; Investigation; Lewy Body Dementia; Maps; Measurement; Measures; Messenger RNA; Methods; Modeling; Molecular; Molecular Profiling; Motor; Neocortex; Neurodegenerative Disorders; Parkinson Disease; Pathology; Pathway interactions; Patients; Predisposition; Prefrontal Cortex; Progressive Supranuclear Palsy; Proteins; Proteome; Resolution; Spatial Distribution; Standardization; Superior temporal gyrus; Techniques; Thick; Time; Tissue Sample; Tissues; Vascular Diseases; Work; age effect; aging brain; brain tissue; cell injury; cell type; cerebrovascular; cohort; computer framework; data integration; genome-wide; human tissue; image registration; imaging Segmentation; limbic-predominant age-related TDP-43 encephalopathy; multimodality; neocortical; normal aging; novel; protein expression; scale up; secondary analysis; single nucleus RNA-sequencing; transcriptome; transcriptomics

PROJECT 1: PROJECT SUMMARY/ABSTRACT Aging is characterized by the accumulation of molecular and cellular damage resulting in decreasing cellular functionality; diseases that are particularly associated with aging include cerebrovascular disease and neurodegenerative diseases. Although focus has been on individual proteinopathies and cerebrovascular defects that occur more frequently with age, little is known about the local effects of aging on gene expression signatures and how these effects impact cellular composition and increase susceptibility to disease. Here, we focus on how ageing alters the cellular environment in three distinct regions of the brain, in patients with minimal or no pathology, that are known to be susceptible to the effects of protein and/or vascular pathologies in later life: superior temporal gyrus, dorsolateral prefrontal cortex, and calcarine cortex. We hypothesize that normal aging will have local and global effects on cell type composition and associated gene expression/molecular signatures, and that understanding these attributes will allow us to form a better understanding of why divergence from this state may result in pathology in these vulnerable regions. The aim of this project is to generate a spatial atlas of normal aging using individuals spanning an age range from 20- 90, all with minimal to no underlying pathology. To achieve this goal, we will use immunohistochemical (4i) and unbiased transcriptomics (10x Visium ST) techniques to generate a large-volume (300-micron thickness) 3-D atlas of three key brain regions vulnerable to pathology in later life from 30 individuals. We aim to derive cell type- and molecular signature-specific maps for each subject, integrating these data into a computational framework to characterize changes in local and global signatures with respect to age. We will then validate high-value associations derived from this framework in a replication cohort of 20 individuals. Using this approach, we hope to provide an unprecedented set of cell type and gene expression signature maps that represent the spectrum of normal aging.

项目1：项目摘要/摘要 衰老的特征是分子和细胞损伤的积累，导致细胞降低 功能；与衰老特别相关的疾病包括脑血管疾病和 神经退行性疾病。尽管重点是单个蛋白质病和脑血管 随着年龄的增长，出现频率更高的缺陷，对衰老对基因表达的局部影响知之甚少 签名以及这些影响如何影响细胞组成并增加对疾病的敏感性。这里， 我们关注衰老如何改变大脑三个不同区域的细胞环境，患有 最小或没有病理，已知容易受到蛋白质和/或血管病理的影响 在后来的生活中：上部颞叶，背侧前额叶皮层和钙质皮质。我们假设这一点 正常衰老将对细胞类型组成和相关基因产生局部和全球影响 表达/分子特征，理解这些属性将使我们形成更好 了解为什么与这种状态的分歧可能导致这些脆弱地区的病理。目的 这个项目的是，使用年龄范围为20- 90，全部最少，没有潜在的病理。为了实现这一目标，我们将使用免疫组织化学（4i） 和无偏的转录组学（10倍visium st），生成大量的（300微米厚度） 三个关键大脑区域的3-D地图集在后来的30个人中容易受到病理的影响。我们旨在得出 每个受试者的细胞类型和分子特异性图，将这些数据整合到计算中 框架以表征与年龄相对于年龄的本地和全球签名变化的框架。然后我们将验证 高价值关联从该框架中得出的20个人的复制队列中得出。使用此 方法，我们希望提供一套前所未有的细胞类型和基因表达签名图 代表正常衰老的光谱。