An Integrative Multi-Omics Approach to Elucidate Sex-Specific Differences in Alzheimers Disease

项目摘要 阿尔茨海默病（Alzheimer's disease，AD）是一种多因素的神经退行性疾病， 多种遗传和环境因素。大量证据令人信服地证明，性是 疾病异质性和生理状态的主要来源。AD风险的性别差异，脆弱性 载脂蛋白（apo）E遗传负荷和AD病理负荷的严重程度。此外 对于这些疾病的直接贡献者来说，性别差异也存在于许多生理和共病方面。 已知是AD风险因素的疾病，最明显的是与年龄相关的炎症。尽管性别差异 在AD的风险中，对遗传负荷的脆弱性和AD病理学负担的严重性已经得到很好的确定， 在男性和女性AD患者中差异介导的分子基础和途径是 仍然知之甚少。AD过程中免疫和炎症反应的差异是另一个原因 疾病异质性的来源;然而，潜在的机制仍然难以捉摸。 精准医疗是一种新兴的疾病预防、早期发现和预防的综合方法。 治疗，其中考虑到遗传学，表观遗传学，性别，环境和 生活方式目前和不断增长的正常和AD大脑的公共组学数据的可用性，包括 基因表达综合，阵列表达和新的国家衰老研究所的加速药物 阿尔茨海默病门户网站（AMP-AD）的合作伙伴关系，沿着新兴的单细胞测序技术 和计算工具，在网络水平上剖析疾病的分子驱动因素，提出了一个独特的新的 有机会质疑apoE 4与性别和炎症在AD发病机制中的相互作用， 基因组、转录组和单细胞水平。 通过利用这一承诺，本提案旨在（1）分析公开可用的大规模 AD患者和年龄匹配对照的转录组数据集，以确定性别和apoE基因型特异性 AD的基因表达特征，（2）分析公开可用的大规模AD基因组数据集 患者和年龄匹配的对照，以确定与男性AD差异相关的基因组区域， 和女性患者，并检查其与apoE基因型的交互作用，（3）利用单一的 核RNA-Seq技术，以检查性别和apoE基因型特异性转录组签名， 建立AD小鼠模型并评估其与人类数据的相关性。我们的目标是专门审问 在小鼠和人类的基因组和转录组水平上的炎症和免疫途径 在我们的三个具体目标中，阐明了这些途径导致疾病的机制， 和基因型特异性差异的男性和女性与AD。拟议的研究结果将摆脱 阐明了可能解释AD发病机制中性别差异的分子途径， turn可以为精准医学诊断和治疗策略提供信息。

PROJECT SUMMARY Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder caused by interactions among multiple genetic and environmental factors. A large body of evidence has convincingly demonstrated that sex is a major source of disease heterogeneity and physiologic status. Sex differences in the risk of AD, vulnerability to apolipoprotein (apo) E genetic load, and severity of AD pathology burden have been established. In addition to these direct contributors to disease, sex-differences also exist for many of the physiological and co-morbid conditions known to be risk factors for AD, most notably age-related inflammation. Although the sex differences in the risk of AD, vulnerability to genetic load and severity of AD pathology burden have been well established, the molecular underpinnings and pathways that are differentially mediated in male and female AD patients are still poorly understood. The difference in immunity and inflammatory response during AD process is another source of the disease heterogeneity; however, the underlying mechanisms remain elusive. Precision medicine is an emerging integrative approach for disease prevention, early detection, and treatment, which takes into account individual variability in genetics, epigenetics, sex, environment, and lifestyle. The current and ever-growing availability of public `omics data of normal and AD brains, including Gene Expression Omnibus, Array Express and the new National Institute of Aging's Accelerating Medicines Partnership for Alzheimer's Disease portal (AMP-AD), along with emerging single cell sequencing technologies and computational tools to dissect molecular drivers of disease at a network level, present a unique new opportunity to query the interactive effects of apoE4 with sex and inflammation on AD pathogenesis at the genomic, transcriptomic and single cell level. By capitalizing on this promise, this proposal aims (1) to analyze publicly available, large-scale transcriptomic datasets of AD patients and age-matched controls to identify sex and apoE genotype-specific gene expression signatures of AD, (2) to analyze publicly available, large-scale genomic datasets of AD patients and age-matched controls to identify genomic regions that are associated with AD differentially in male and female patients and examine their interactive effects with apoE genotypes, and (3) to leverage single nucleus RNA-Seq technology to examine sex and apoE genotype specific transcriptomic signatures in an established mouse model of AD and evaluate their relevance to human data. We aim to specifically interrogate inflammatory and immune pathways both on the genomic and transcriptomic level in mice and humans throughout our three specific aims to elucidate the mechanisms by which these pathways lead to the disease and genotype specific differences in men and women with AD.The outcomes of the proposed studies will shed light on the molecular pathways that might explain the sex differences in the pathogenesis of AD and which in turn can inform precision medicine diagnostic and therapeutic strategies.