Dissecting the role of sex-linked genes and APOE e4 risk in AD

剖析 AD 中性相关基因和 APOE e4 风险的作用

• 批准号: 10677855
• 负责人: Christine M. Disteche
• 金额: $ 119.05万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677855
• 关键词: 3-Dimensional; Acceleration; Address; Age; Age Factors; Alleles; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-Protein; Apolipoprotein E; Autopsy; Bioinformatics; Biological Assay; Brain; Candidate Disease Gene; Cell Culture Techniques; Cell Line; Cell model; Cells; Cellular Assay; Complex; Computational Biology; Data; Dementia; Development; Disease; Disease Progression; Dose; Environmental Risk Factor; Epigenetic Process; Event; Exclusion; Female; Functional disorder; Gene Combinations; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Gene Modified; Genes; Genetic; Genotype; Goals; Gonadal Steroid Hormones; Health; Hormonal; Hormones; Human; Immune; Impaired cognition; In Vitro; Individual; Inflammation; Inflammatory Response; Late Onset Alzheimer Disease; Life Style; Ligands; Link; Longevity; Metabolic Pathway; Methods; Microglia; Molecular; Myelogenous; Nerve Degeneration; Neurobiology; Neuroimmune; Neurons; Organoids; Pathogenesis; Pathologic; Pathology; Pathway interactions; Phenotype; Ploidies; Predisposition; Protocols documentation; Research; Risk; Risk Factors; Role; Sex Bias; Sex Chromosomes; Sex Differences; Sex Factors; Small Nuclear RNA; Structure; Testing; Tissues; Variant; Woman; X Chromosome; X Inactivation; apolipoprotein E-4; brain cell; brain tissue; cell type; cerebral atrophy; cognitive function; cohort; data integration; disease phenotype; dosage; effective therapy; gene interaction; genetic risk factor; genetic variant; genome wide association study; genome-wide analysis; high risk; human tissue; immune function; induced pluripotent stem cell; innovation; insight; knock-down; lifetime risk; male; men; mosaic loss; neuroinflammation; neuropathology; novel; overexpression; receptor; response; sex; single nucleus RNA-sequencing; stem cell model; synergism; tool; transcriptomics; two-dimensional

Project Summary Women have a higher lifetime risk of developing Alzheimer's disease (AD) than men. This increased risk is not fully explained by differences in longevity, hormones or brain structure. Women who carry at least one copy of the APOEɛ4 allele, the strongest genetic risk factor for late onset AD (LOAD), have accelerated neuropathology. However, some studies suggest a faster decline in men, suggesting that sex bias may differ depending on the stage of the disease. Here, we will investigate how the sex chromosome complement and sex-linked genes influences sex differences in onset and progression of LOAD. Genome-wide association studies have identified genetic and epigenetic risk factors for LOAD, but the sex-chromosomes are often excluded in these studies meaning there is a lack of data on sex-linked genes. Males have unique Y-linked genes and females have higher expression of genes that escape X inactivation. Interestingly, many of the escape genes are related to immune function and neuroinflammation is a hallmark of AD, suggesting that these genes may directly contribute to disease progression. To address the impact of sex-linked genes combined with APOEɛ4 alleles on neuroinflammation in LOAD we will use unique cellular models and AD tissue for leveraging integrated omics and functional studies. We will evaluate the functional roles of sex chromosomes and sex-linked genes in brain cell types using human induced pluripotent stem cell (hiPSC) models. We have derived isogenic pairs of hiPSCs with a different number of sex chromosomes on the same genetic background (XXY/XY or XXX/X). These new hiPSC lines minimize variability between individuals, as well as environmental or hormonal confounders. We will generate isogenic pairs of these lines with ɛ3/3 or ɛ3/4 alleles by gene editing. After differentiation of hiPSC into neurons, microglia, and brain organoids we will employ a combination of `omic' analyses and functional assays focusing on neuroinflammation and neurodegeneration. This approach will identify sex-linked candidate genes, which will be tested for dosage effects by knockdown and overexpression. These in vitro studies will be validated in human tissue collected by the Precision Neuropathology Core from our Alzheimer's Disease Research Center brain bank. Using pathologically characterized AD brains we will employ myeloid-specific single-nucleus RNA sequencing to determine the effects of sex and APOEɛ4 genotypes on microglial subtypes and neuroimmune gene expression. Our new team combines expertise in hiPSC modeling, sex-linked genes, neuroinflammation, `omic analyses and neuropathology. This integrative study will help understand sex-specific genetic factors and how those factors interact with APOEɛ4 risk to modulate cellular dysfunction and pathology, thus providing novel insights into how to tailor a more effective treatment for AD.

项目概要 女性一生中罹患阿尔茨海默病 (AD) 的风险高于男性。这种增加的风险并不 寿命、激素或大脑结构的差异可以充分解释这一点。至少携带一份该文件的女性 APOEɛ4 等位基因是晚发性 AD (LOAD) 最强的遗传风险因素，可加速神经病理学的发展。 然而，一些研究表明，男性的下降速度更快，这表明性别偏见可能因性别而异。 疾病的阶段。在这里，我们将研究性染色体互补和性连锁基因如何 影响 LOAD 发生和进展的性别差异。全基因组关联研究发现 LOAD 的遗传和表观遗传风险因素，但这些研究中通常排除性染色体 这意味着缺乏与性别相关的基因的数据。男性有独特的Y连锁基因，女性有更高的 逃避 X 失活的基因的表达。有趣的是，许多逃逸基因与免疫有关 功能和神经炎症是 AD 的标志，表明这些基因可能直接导致疾病 进展。探讨性别连锁基因与 APOEɛ4 等位基因相结合对神经炎症的影响 LOAD 我们将使用独特的细胞模型和 AD 组织来利用综合组学和功能研究。 我们将使用人类评估性染色体和性连锁基因在脑细胞类型中的功能作用 诱导多能干细胞（hiPSC）模型。我们衍生出了不同数量的同基因 hiPSC 对 具有相同遗传背景（XXY/XY 或 XXX/X）的性染色体。这些新的 hiPSC 系最大限度地减少了 个体之间的差异，以及环境或荷尔蒙的混杂因素。我们将生成同基因对 通过基因编辑使这些品系具有 ɛ3/3 或 ɛ3/4 等位基因。 hiPSC 分化为神经元、小胶质细胞和 对于大脑类器官，我们将结合“组学”分析和功能分析，重点关注 神经炎症和神经变性。这种方法将鉴定与性别相关的候选基因，这将是 通过敲低和过表达来测试剂量效应。这些体外研究将在人体中得到验证 精密神经病理学核心从我们的阿尔茨海默病研究中心脑库收集的组织。 使用具有病理学特征的 AD 大脑，我们将采用骨髓特异性单核 RNA 测序来 确定性别和 APOEɛ4 基因型对小胶质细胞亚型和神经免疫基因表达的影响。 我们的新团队结合了 hiPSC 建模、性连锁基因、神经炎症、组学分析和 神经病理学。这项综合研究将有助于了解性别特异性遗传因素以及这些因素如何影响 与 APOEɛ4 风险相互作用来调节细胞功能障碍和病理学，从而为如何 为 AD 制定更有效的治疗方法。