Multimodal single-cell genomic and epigenomic analyses elucidate Alzheimer’s sexual dimorphism in human immune systems aging

多模式单细胞基因组和表观基因组分析阐明了人类免疫系统衰老中的阿尔茨海默氏症性别二态性

• 批准号: 10467465
• 负责人: Lynn Bekris
• 金额: $ 120.58万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-05 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10467465
• 关键词: AD transgenic mice; ATAC-seq; Address; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer’s disease biomarker; American; Bioinformatics; Biological Assay; Biology; Blood; Brain; Cause of Death; Cell Nucleus; Cells; Clinic; Clinical; Combined Modality Therapy; Data; Databases; Dementia; Dementia with Lewy Bodies; Development; Diagnosis; Disease; Disease Progression; Drug Combinations; Electronic Health Record; Enhancers; Erectile dysfunction; Evaluation; Female; Foundations; Funding; Gene Expression; Genes; Genetic; Genetic Transcription; Genomics; Goals; Heterogeneity; Human; Immune; Immune response; Immune system; Immunomodulators; Incidence; Individual; Inflammation; Inflammatory; Mediating; Methodology; Microglia; Molecular; Morbidity - disease rate; Myeloid-derived suppressor cells; National Institute on Aging; Network-based; Neuroimmune; Outcome; Pathogenesis; Patients; Penetration; Peripheral; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacoepidemiology; Pharmacological Treatment; Pharmacotherapy; Phosphodiesterase Inhibitors; Play; Predisposition; Prevalence; Preventive; Prognosis; Regimen; Regulator Genes; Reporting; Research; Retrospective cohort; Role; Sampling; Sex Differences; Small Nuclear RNA; System; Systems Biology; Technology; Testing; Therapeutic; United States; Universities; Validation; Variant; Washington; Woman; base; care costs; cell type; clinical development; clinical efficacy; clinically relevant; cohort; cost; differential expression; epidemiology study; epigenome; epigenomics; functional genomics; genetic signature; genome wide association study; genomic data; genomic locus; granulocyte; human data; human interactome; improved; individualized medicine; innovation; male; mild cognitive impairment; molecular targeted therapies; mortality; mouse model; multimodality; multiple omics; neuropathology; next generation; novel; novel therapeutics; pre-clinical; precision medicine; prevent; promoter; sex; sexual dimorphism; side effect; sildenafil; single cell analysis; single-cell RNA sequencing; symptomatic improvement; systemic inflammatory response; therapeutic development; transcription factor; transcriptome; transcriptome sequencing; transcriptomics; translational study; treatment response

PROJECT SUMMARY Alzheimer’s disease (AD) is sexually dimorphic in its prevalence, incidence, symptomology, and neuropathology, but the mechanisms underlying these sex differences are not well understood. While sex differences in susceptibility to inflammation and AD progression have been reported, the relationship between local and systemic inflammation and sex differences remains to be determined. Our preliminary single-cell genomic analyses have identified sex-specific microglial gene signatures in AD patient brains. Bioinformatics analyses of single-cell transcriptomic data of human peripheral blood mononuclear cells (PBMCs) imply that multiple sex- specific, candidate pro-inflammatory genes are highly expressed in myeloid-derived suppressor cells (MDSCs) in AD. We therefore posit that an interplay between microglia and systematic inflammatory mechanisms (termed the “peripheral-central neuro-immune interactome”) exists and that understanding this system will be essential to improve the mechanistic elucidation of AD pathogenesis in a sex-specific manner. Recent advances of multimodal single-cell genomic and epigenomic analyses have shown the potential to provide a comprehensive understanding of the neuro-immune and peripheral immune systems underlying sex differences in AD. Integration of the single-cell transcriptome, epigenome, the human interactome, along with large-scale genetic loci from genome-wide association studies are essential for such identification. To address this hypothesis, our short-term goal is to identify next-generation immune modulators for AD sex differences and molecularly targeted treatments for male and female patients with AD. We will leverage large-scale single- cell genomic and epigenomic data generated from human brains and bloods with varying degrees of AD pathology available at our two National Institute of Aging (NIA)-funded Alzheimer's Disease Research Center (ADRCs) at the Cleveland Clinic and University of Washington. Aim 1 will test the hypothesis that central neuro- immune transcriptional networks mediate sex differences in AD using single-nucleus genomic and epigenomic analyses of human brains. Aim 2 will test the hypothesis that cell type-specific central neuro-immune and peripheral immune interactome network changes in AD pathogenesis act in a sex-specific manner. In parallel, we will utilize network-based, single-cell multi-omics analyses in AD transgenic mouse models to identify immune cell type-specific promoters and enhancers that encode sex-specific master gene regulatory networks for AD. Aim 3 will test the hypothesis that sex-specific, peripheral-central neuro-immune interactome networks in AD can be targeted via pharmacologic treatment to reduce AD progression. We will use our well-established network proximity methodologies to identify sex-specific repurposable drugs that influence the immune response using mouse models and validate preclinical findings in large patient databases using state-of-the-art retrospective cohort observations. We believe that this highly innovative and integrated approach offers the possibility of achieving our long-term goal of greatly accelerating personalized sex-specific treatments for AD.

项目摘要 阿尔茨海默氏病（AD）在患病率，发病率和神经病理学上是性二态性的， 但是这些性别差异的基础机制尚未得到充分理解。 据报道了对炎症和广告进展的敏感性，局部之间的关系 系统性炎症和性别差异尚待确定。 分析已经确定了AD患者大脑中的性别特异性小胶质细胞特异性 人外周血单核细胞（PBMC）的单细胞转录数据暗示多个性别 特异性候选促炎基因在髓样衍生的抑制细胞（MDSC）中高高表达 因此，我们对小胶质细胞和系统的炎症机制进行了前景（称为） 存在“外围中心神经免疫互动组”），并且该系统将是 对于以性别特异性的方式提高AD发病机理的机械化至关重要 多模式的单细胞基因组和表观基因组分析表明，有可能提供A 对性别基础的神经膜和周围免疫系统的全面理解 AD的差异。 全基因组关联研究的大规模遗传基因座对于这种鉴定至关重要。 这个假设，我们的短期目标是确定下一代IMUNE调节剂的广告性别差异 和针对AD的男性和女性患者的分子治疗。 细胞基因组和表观基因组数据由人的大脑和血液产生不同程度的血液 病理学可在我们的两个国家老化研究所（NIA）资助的阿尔茨海默氏病研究中心可用 （ADRC）在克利夫兰诊所和华盛顿大学。 免疫转录网络介导性别差异性别差异单核基因组和表观基因组学 对人的大脑的分析将测试细胞类型的中央神经元素的假设 AD发病机理的外围Imune相互作用网络以性别特异性的方式变化。 我们将在AD转基因鼠标模型中利用基于网络的单细胞多摩斯分析来识别免疫 针对AD的性别特异性主基因调控网络的细胞类型特异性启动子和增强子。 AIM 3将检验以下假设：AD中的性别特异性，外围中心神经免疫相互作用网络 可以通过药物信任来降低AD的进展。 接近方法可以识别使用使用 鼠标模型并使用最新回顾性验证大型患者数据库中的临床前发现 队列观察。我们认为创新和综合方法提供了 实现了我们的长期目标，即为AD加速了个性化的特定治疗方法。