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: 9896409
• 负责人: Towfique Raj
• 金额: $ 46.61万
• 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/9896409
• 关键词: 3-Dimensional; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid beta-Protein; Animal Model; Apoptotic; Biological Models; Brain; Catalogs; Cell physiology; Cells; Central Nervous System Diseases; Coculture Techniques; Communities; Data; Data Set; Dementia; Development; Disease; Foundations; Future; Gene Expression; Genes; Genetic; Genetic Diseases; Genetic Risk; Genetic Transcription; Genetic study; Genomics; Genotype; Goals; Human; Immune; Immune system; Impaired cognition; Individual; Inflammatory; Inflammatory Response; Innate Immune System; Interferons; Knowledge; Lead; Lipoproteins; Maps; Microglia; Modeling; Molecular; Mouse Cell Line; Myelin; Myelogenous; Myeloid Cells; Nerve Degeneration; Network-based; Neuraxis; Neurodegenerative Disorders; Organoids; Pathogenesis; Pathway Analysis; Pathway interactions; Peripheral; Phagocytes; Phagocytosis; Play; Process; Quantitative Trait Loci; RNA Splicing; Regulator Genes; Resources; Risk; Risk Factors; Role; SPI1 gene; Sampling; Signal Pathway; Spliced Genes; Stimulus; Susceptibility Gene; TREM2 gene; Variant; Work; age related; age related neurodegeneration; aged; aging brain; base; brain cell; brain tissue; cohort; disorder risk; genetic variant; genomic locus; induced pluripotent stem cell; insight; monocyte; mouse model; nervous system development; normal aging; novel; pathogen; protein expression; protein function; rare variant; response; risk variant; transcriptome; transcriptomics

PROJECT SUMMARY 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. By combining the unique expertise of the two PIs in the isolation and culture of human microglia, as well as advanced computational genomics analysis of human myeloid immune cells. 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. These profiles will be validated in new microglia transcriptomes from an independent cohort of 15 donors to determine the response of these samples to interferon and Aβ and sort subsets with different phagocytic capacity. 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.

项目摘要 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。尽管广告的基础机制仍然很大未知，但很明显，衰老 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 大脑的免疫细胞，在中枢神经正常衰老的过程中起着至关重要的作用 AD的系统和开发。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，并且 网络分析表明，这些基因座的主要部分在髓样免疫系统中起作用。在 此外，在老年人的小胶质细胞中发现了基因表达的变化 小鼠模型的小胶质细胞。这些小胶质细胞的变化如何促进AD尚不清楚。回答这个 问题是了解AD中涉及的机制的重要一步。此外，这可能 导致用于治疗AD和相关神经退行性疾病的新型靶标。长期 该项目的目标是加深我们对小胶质细胞在AD中的作用的见解，并鉴定与小胶质细胞相关 治疗中枢神经系统与年龄有关的疾病的靶标。迈向的重要第一步 达到这个目标是了解广告中发现的小胶质细胞的变化告诉我们 基因和蛋白质表达和功能的变化。因此，这项研究的总体目标是 确定与基线和在基线上改变小胶质细胞基因表达的广告相关的常见遗传变异 对炎症刺激的反应。通过将两个PI的独特专业知识结合在隔离和文化中 人类小胶质细胞的人类小胶质细胞以及对人髓样免疫细胞的高级计算基因组学分析。在 AIM 1，我们将使用264个现有的小胶质细胞样本，以前我们已经隔离了103个区域 大脑供体生成基因型和转录组谱。通过将这些数据与现有的小胶质细胞相结合 转录组数据集，我们将能够生成与AD相关遗传基因座如何影响基因的地图 表达（或表达定量性状基因座，EQTL）和剪接（SQTL）。在AIM 2中，我们将使用干扰素 （IFN）刺激的小胶质细胞样品，我们先前已收集以表征AD相关的风险 变体改变了IFN刺激的转录组变化。这些配置文件将在新的小胶质细胞中得到验证 来自15个捐助者的独立队列的转录组，以确定这些样品对 干扰素和Aβ，并分类具有不同吞噬能力的子集。转录组轮廓和 将在这两个目标中生成的表达和剪接QTL将公开可用，我们 将把这些概况应用于老年和AD脑组织和周围的非常大的基因数据集 研究基因表达如何变化的单核细胞与小胶质细胞功能的变化有关。在一起，我们 预计这项研究将为小胶质细胞中的分子机制提供关键信息，将AD遗传学桥接起来， 为模型系统中的未来机械研究奠定了基础。