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

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，导致细胞数量减少 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。尽管焦点一直集中在个别蛋白病变和脑血管疾病上 随着年龄的增长，缺陷发生的频率更高，但对衰老对基因表达的局部影响知之甚少 以及这些效应如何影响细胞组成和增加对疾病的易感性。这里, 我们专注于衰老如何改变大脑三个不同区域的细胞环境，在患有 轻微或无病理，已知易受蛋白质和/或血管病变影响 晚年：颞上回、背外侧前额叶皮质和距骨皮质。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/分子签名，了解这些属性将使我们能够形成更好的 理解为什么偏离这种状态可能会导致这些脆弱区域的病理。其目的是 这个项目的目的是使用年龄范围从20岁到20岁的人来生成正常老龄化的空间地图集 90岁，所有人都有轻微的甚至没有潜在的病理。为了实现这一目标，我们将使用免疫组织化学(4I) 和无偏转录学(10倍维西姆ST)技术，以产生大容量(300微米厚度) 30个人晚年易受病理影响的三个关键大脑区域的3D图谱。我们的目标是从 每个受试者的细胞类型和分子特征特定的地图，将这些数据集成到计算 描述本地和全球签名相对于年龄的变化的框架。然后我们将验证 在20个人的重复队列中，从这个框架中衍生出高价值的关联。使用这个 我们希望提供一套史无前例的细胞类型和基因表达特征图谱， 代表正常衰老的光谱。

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.