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: 10299469
• 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/10299469
• 关键词: 3-Dimensional; Address; Age; Age Factors; Alleles; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid beta-Protein; Apolipoprotein E; Autopsy; Bioinformatics; Biological Assay; Brain; Candidate Disease Gene; Cell Culture Techniques; Cell Line; Cell Nucleus; Cell model; Cells; Cellular Assay; Chromosomes, Human, 16-18; Complex; Computational Biology; Data; Dementia; Development; Disease; Disease Progression; Dose; Environmental Risk Factor; Epigenetic Process; Event; Female; Functional disorder; Gene Expression; Gene Expression Profile; 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; Lead; Life Style; Ligands; Link; Longevity; Metabolic Pathway; Methods; Microglia; Molecular; Mosaicism; Myelogenous; Nerve Degeneration; Neurobiology; Neuroimmune; Neurons; Organoids; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; 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; disease phenotype; dosage; effective therapy; genetic risk factor; genetic variant; genome wide association study; high risk; human tissue; immune function; induced pluripotent stem cell; innovation; insight; knock-down; lifetime risk; male; men; neuroinflammation; neuropathology; novel; overexpression; receptor; response; sex; stem cell model; synergism; tool; transcriptome sequencing; 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.

项目摘要 女性患阿尔茨海默病(AD)的风险终生高于男性。这种增加的风险并不是 这完全可以用寿命、荷尔蒙或大脑结构的不同来解释。携带至少一份 载脂蛋白Eɛ4等位基因是晚发性AD(LOAD)的最强遗传危险因素，它加速了神经病理。 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会有所不同，这取决于 处于疾病的阶段。在这里，我们将研究性染色体是如何补充和性相关基因的 影响负荷发生和进展的性别差异。全基因组关联研究发现 遗传和表观遗传的危险因素，但性染色体经常被排除在这些研究中 这意味着缺乏与性别相关的基因数据。男性有独特的Y连锁基因，女性有更高的 逃脱X失活的基因的表达。有趣的是，许多逃逸基因都与免疫有关。 功能和神经炎症是阿尔茨海默病的一个标志，这表明这些基因可能直接导致疾病 进步。目的：探讨性连锁基因与载脂蛋白Eɛ4等位基因结合对大鼠神经炎症的影响。 Load我们将使用独特的细胞模型和AD组织来利用集成的组学和功能研究。 我们将使用人类来评估性染色体和性相关基因在脑细胞类型中的功能作用 诱导多能干细胞(HiPSC)模型。我们已经获得了具有不同数量的hPSCs的等基因对 性染色体的遗传背景相同(XXY/XY或XXX/X)。这些新的HiPSC系列将 个体之间的可变性，以及环境或激素的混杂因素。我们将产生同基因对 对含有ɛ3/3或ɛ3/4等位基因的品系进行基因编辑。在HiPSC分化为神经元、小胶质细胞和 脑有机化合物，我们将使用‘组学’分析和功能分析相结合的方法，重点是 神经炎症和神经变性。这种方法将识别与性别相关的候选基因，这将是 通过基因敲除和过度表达来测试剂量效应。这些体外研究将在人类身上得到验证。 由精密神经病理中心从我们的阿尔茨海默病研究中心脑库收集的组织。 使用病理特征的阿尔茨海默病大脑，我们将使用髓系特异性单核RNA测序来 确定性别和载脂蛋白ɛ4基因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、性相关基因、神经炎症、经济学分析和 神经病理学。这项综合研究将有助于理解性别特有的遗传因素以及这些因素是如何 与载脂蛋白Eɛ4风险相互作用，调节细胞功能障碍和病理，从而为如何 为AD量身定做一种更有效的治疗方法。