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 衰老的特点是分子和细胞损伤的积累，导致细胞活力下降 功能性；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。尽管焦点一直集中在个体蛋白质病和脑血管病上 随着年龄的增长，缺陷更频繁地发生，但人们对衰老对基因表达的局部影响知之甚少 特征以及这些效应如何影响细胞组成并增加对疾病的易感性。这里， 我们关注衰老如何改变患有以下疾病的患者大脑三个不同区域的细胞环境： 已知易受蛋白质和/或血管病理影响的病理学最少或无病理学 晚年：颞上回、背外侧前额皮质和距状皮质。我们假设 正常衰老会对细胞类型组成和相关基因产生局部和整体影响 表达/分子特征，并且理解这些属性将使我们能够形成更好的 了解为什么偏离这种状态可能会导致这些脆弱区域出现病变。目的 该项目的目的是利用 20-20 岁的个体生成正常衰老的空间图集。 90，所有潜在病理都极少甚至没有。为了实现这一目标，我们将使用免疫组织化学 (4i) 和无偏转录组学 (10x Visium ST) 技术来生成大体积（300 微米厚度） 30 个人在晚年生活中容易出现病理变化的三个关键大脑区域的 3-D 图谱。我们的目标是导出 每个受试者的细胞类型和分子特征特定图，将这些数据整合到计算中 描述本地和全球特征随年龄变化的框架。然后我们将验证 在 20 人的复制队列中，从该框架中得出高价值关联。使用这个 方法，我们希望提供一套前所未有的细胞类型和基因表达特征图谱， 代表正常衰老的范围。