The impact of Alzheimer's disease susceptibility alleles on microglia transcriptome

阿尔茨海默病易感等位基因对小胶质细胞转录组的影响

• 批准号: 10162110
• 负责人: Towfique Raj
• 金额: $ 13.32万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10162110
• 关键词: Administrative Supplement; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease risk; Biological Models; Brain; Cells; Central Nervous System Diseases; Data; Data Set; Dementia; Disease; Foundations; Future; Gene Expression; Genes; Genetic Diseases; Genetic study; Genotype; Goals; Immune; Immune system; Impaired cognition; Individual; Inflammatory; Interferons; Lead; Maps; Microglia; Molecular; Myelogenous; Neuraxis; Neurodegenerative Disorders; Pathway Analysis; Peripheral; Play; Process; Publishing; Quantitative Trait Loci; RNA Splicing; Risk; Risk Factors; Role; Sampling; Stimulus; Susceptibility Gene; age related; age related neurodegeneration; aged; aging brain; brain cell; brain tissue; genetic variant; genomic locus; insight; monocyte; mouse model; nervous system development; normal aging; novel; protein expression; protein function; response; risk variant; transcriptome; transcriptomics

Abstract Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by progressive cognitive decline and dementia. Although the mechanisms underlying AD are still largely unknown, it is clear that aging of the brain is a key risk factor for this disease. Several lines of evidence indicate that microglia, the myeloid immune cells of the brain, play a crucial role in the processes involved in normal aging of the central nervous system and development of AD. Recent genetic studies have identified over twenty novel AD risk loci, and network analysis have shown that a major part of these loci play a role in the myeloid immune system. In addition, gene expression changes have been found in microglia of aged individuals, subjects with AD and in microglia in mice models for AD. How these microglia changes contribute to AD is not yet clear. Answering this question is an important step towards understanding the mechanisms involved in AD. In addition, this could lead to unravelling novel targets for treatment of AD and related neurodegenerative disorders. The long-term goal of this project is to deepen our insight into the role of microglia cells in AD and to identify microglia-related targets for treatment of age-related disorders of the central nervous system. An important first step towards reaching this goal is to understand what the changes that have been found microglia in AD tell us in terms of changes in gene and protein expression and functions. The overall objective of this study is therefore to identify the AD-associated common genetic variants that alters microglia gene expression at baseline and in response to inflammatory stimuli. In Aim 1, we will use 264 existing microglia samples that we have previously isolated of different regions of 103 brain donors to generate genotype and transcriptome profiles. By combining these data with existing microglia transcriptomic datasets, we will be able to generate a map of how AD-associated genetic loci influence gene expression (or expression quantitative trait loci, eQTL) and splicing (sQTL). In aim 2, we will use interferon (IFN) stimulated microglial samples that we have previously collected to characterize how AD-associated risk variants alter IFN- stimulated transcriptome changes. In this administrative supplement, we plan to sequence an additional 82 microglial samples that we have isolated and stored. This would increase the number of samples in our study to 343, which is much greater than any of the studies currently published. The transcriptome profiles and expression and splicing QTL that will be generated in these two aims will be made publically available and we will apply these profiles to very large available gene datasets on aged and AD brain tissue and peripheral monocytes to investigate how gene expression changes relate to changes in microglia function. Together, we expect that this study will provide key information bridging AD genetics to molecular mechanisms in microglia, setting the stage for future mechanistic studies in model systems.

抽象的 阿尔茨海默氏病（AD）是一种与年龄有关的神经退行性疾病，其特征是进行性认知 衰落和痴呆。尽管AD的基础机制仍然很大未知，但很明显， 大脑是这种疾病的关键危险因素。几条证据表明小胶质细胞，髓样免疫 大脑细胞，在中枢神经系统正常衰老的过程中起着至关重要的作用 广告的开发。最近的遗传研究已经确定了二十多种新颖的AD风险基因座和网络分析 已经表明，这些基因座的主要部分在髓样免疫系统中起作用。另外，基因表达 在老年个体的小胶质细胞中发现了变化 广告。这些小胶质细胞的变化如何促进AD尚不清楚。回答这个问题是重要的一步 要了解AD中涉及的机制。此外，这可能导致揭开新的目标 用于治疗AD和相关神经退行性疾病。该项目的长期目标是加深我们 深入了解小胶质细胞在AD中的作用，并鉴定与小胶质细胞相关的靶标以治疗年龄相关的靶标 中枢神经系统的疾病。实现这一目标的重要第一步是了解什么 AD中发现的小胶质细胞的变化告诉我们基因和蛋白质表达的变化 和功能。因此，这项研究的总体目的是确定与广告相关的共同遗传 在基线和炎症刺激响应基线时改变小胶质细胞表达的变体。在AIM 1中，我们 将使用264个现有的小胶质细胞样品，我们以前已经隔离了103个大脑供体的不同区域 生成基因型和转录组轮廓。通过将这些数据与现有的小胶质细胞转录组相结合 数据集，我们将能够生成一张映射，介绍与AD相关的遗传基因座如何影响基因表达（或 表达定量性状基因座，EQTL）和剪接（SQTL）。在AIM 2中，我们将使用刺激的干扰素（IFN） 我们以前收集过的小胶质细胞样品表征了与广告相关的风险变异的改变 刺激的转录组变化。在这种行政补充中，我们计划再对82进行排序 我们已经隔离和存储的小胶质样品。这将使我们研究中的样本数量增加到 343，比目前发表的任何研究都要大得多。转录组轮廓和表达 并将在这两个目标中生成的剪接QTL公开可用，我们将申请 这些对非常大的可用基因数据集的剖面以及AD脑组织和周围单核细胞的概况 研究基因表达的变化与小胶质细胞功能的变化有关。在一起，我们期望这 研究将为小胶质细胞中的分子机制提供关键信息，将AD遗传学桥接为阶段 用于模型系统中的未来机械研究。