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 阿尔茨海默病（AD）是一种与年龄相关的神经退行性疾病，其特征是进行性认知障碍 衰退和痴呆。尽管 AD 的发病机制尚不清楚，但很明显，衰老与 AD 相关。 大脑是这种疾病的关键危险因素。多项证据表明，小胶质细胞（骨髓免疫细胞） 大脑细胞在中枢神经系统正常衰老过程中发挥着至关重要的作用 AD的发展。最近的遗传学研究已经确定了二十多个新的 AD 风险位点，并进行了网络分析 已经表明这些基因座的主要部分在骨髓免疫系统中发挥作用。此外，基因表达 在老年人、AD 受试者和小鼠模型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导致 AD 尚不清楚。回答这个问题是重要的一步 以了解 AD 所涉及的机制。此外，这可能会导致揭示新的目标 用于治疗 AD 和相关的神经退行性疾病。该项目的长期目标是深化我们的 深入了解小胶质细胞在 AD 中的作用，并确定小胶质细胞相关靶点来治疗与年龄相关的疾病 中枢神经系统疾病。实现这一目标的重要第一步是了解什么 AD 中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，本研究的总体目标是确定与 AD 相关的常见遗传基因。 改变基线和响应炎症刺激的小胶质细胞基因表达的变异。在目标 1 中，我们 将使用我们之前从 103 名大脑捐赠者的不同区域分离出的 264 个现有小胶质细胞样本 生成基因型和转录组图谱。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 AD 相关基因位点如何影响基因表达（或 表达数量性状位点（eQTL）和剪接（sQTL）。在目标 2 中，我们将使用干扰素 (IFN) 刺激 我们之前收集的小胶质细胞样本用于表征 AD 相关风险变异如何改变 IFN- 刺激转录组变化。在本行政补充文件中，我们计划对另外 82 个 我们分离并储存的小胶质细胞样本。这将增加我们研究中的样本数量 343，这比目前发表的任何研究都要大得多。转录组概况和表达 这两个目标将产生的剪接QTL将公开，我们将申请 将这些概况转化为有关老年和 AD 脑组织和外周单核细胞的大量可用基因数据集 研究基因表达变化与小胶质细胞功能变化的关系。我们共同期待这 研究将提供连接 AD 遗传学和小胶质细胞分子机制的关键信息，奠定基础 用于模型系统的未来机理研究。