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.

项目摘要 女性患阿尔茨海默氏病（AD）的终生风险高于男性。这种增加的风险不是 寿命，激素或大脑结构的差异充分解释。携带至少一份副本的女性 ApoEɛ4等位基因是延迟发作AD（负载）的强遗传危险因素，具有加速神经病理学。 但是，一些研究表明，男性的下降速度更快，表明性偏见可能因 疾病的阶段。在这里，我们将研究性别染色体的完成和性别连接基因 影响负载发作和进展的性别差异。全基因组关联研究已经确定 负载的遗传和表观遗传危险因素，但性别染色体通常在这些研究中被排除在外 这意味着缺乏有关性别连接基因的数据。雄性具有独特的Y连锁基因，女性具有更高的 逃脱X失活的基因的表达。有趣的是，许多逃生基因与免疫有关 功能和神经炎症是AD的标志，表明这些基因可能直接有助于疾病 进展。解决与apoeɛ4等位基因联合性基因对神经炎症的影响 负载我们将使用独特的细胞模型和AD组织来利用综合的OMIC和功能研究。 我们将使用人类评估性别染色体和性别连接基因的功能作用 诱导多能干细胞（HIPSC）模型。我们衍生出具有不同数字的hipsc的等源性对 在相同遗传背景（XXY/XY或XXX/X）上的性染色体的。这些新的HIPSC线最小化 个体以及环境或荷尔蒙混杂因素之间的差异。我们将生成等生成对 在具有基因编辑的ɛ3/3或ɛ3/4等位基因的这些线中。将hipsc分化为神经元，小胶质细胞和 大脑器官我们将采用“ OMIC”分析和功能分析的组合 神经炎症和神经变性。这种方法将识别与性别联系的候选基因，这将是 通过敲低和过表达测试了剂量效应。这些体外研究将在人类中得到验证 由我们阿尔茨海默氏病研究中心脑库的精确神经病理学核心收集的组织。 使用病理表征的广告大脑，我们将采用髓样特异性单核RNA测序 确定性别和APOEɛ4基因型对小胶质细胞亚型和神经免疫性基因表达的影响。 我们的新团队结合了HIPSC建模，性别联系基因，神经炎症，``OMIC分析''的专业知识 神经病理学。这项综合研究将有助于了解特定的性别遗传因素以及这些因素如何 与APOEɛ4相互作用以调节细胞功能障碍和病理学，从而提供有关如何进行的新见解。 为AD量身定制更有效的治疗方法。