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 阿尔茨海默病（AD）在其患病率、发病率、病理学和神经病理学方面具有性别二态性， 但这些性别差异背后的机制尚不清楚。虽然性别差异在 已经报道了对炎症和AD进展的易感性，局部和 全身炎症和性别差异仍有待确定。我们初步的单细胞基因组 分析已经鉴定了AD患者脑中的性别特异性小胶质细胞基因特征。生物信息学分析 人外周血单核细胞（PBMC）的单细胞转录组学数据表明， 特异性的候选促炎基因在髓源性抑制细胞（MDSC）中高度表达 在AD中。因此，我们认为，小胶质细胞和系统性炎症机制（称为 “外周-中枢神经-免疫相互作用组”）的存在， 这对于以性别特异性方式改善AD发病机制的机制阐明至关重要。最新进展 多模式单细胞基因组和表观基因组分析显示出提供 全面了解神经免疫和外周免疫系统的潜在性别 AD的差异。整合单细胞转录组、表观基因组、人类相互作用组，沿着 来自全基因组关联研究的大规模遗传基因座对于这种鉴定是必不可少的。解决 根据这一假设，我们的短期目标是确定下一代AD性别差异的免疫调节剂 以及针对男性和女性AD患者的分子靶向治疗。我们将利用大规模的单一- 从患有不同程度AD的人脑和血液中产生的细胞基因组和表观基因组数据 病理学可在我们的两个国家老龄化研究所（NIA）资助的阿尔茨海默病研究中心 （ADRCs）在克利夫兰诊所和华盛顿大学。目的1将检验中枢神经系统- 利用单核基因组和表观基因组免疫转录网络介导AD性别差异 分析人类大脑。目的2将检验细胞类型特异性中枢神经免疫和 外周免疫相互作用体网络在AD发病机制中的变化以性别特异性方式起作用。同时， 我们将在AD转基因小鼠模型中利用基于网络的单细胞多组学分析来鉴定免疫相关性。 细胞类型特异性启动子和增强子，其编码AD的性别特异性主基因调控网络。 目的3将验证AD中性别特异性的外周-中枢神经-免疫相互作用组网络的假说 可通过药物治疗靶向降低AD进展。我们将利用我们完善的网络 使用邻近方法来识别影响免疫反应的性别特异性可再利用药物， 使用最先进的回顾性研究，在大型患者数据库中建立小鼠模型并验证临床前发现 队列观察。我们认为，这种高度创新和综合的办法提供了以下可能性： 实现我们的长期目标，大大加快个性化的性别特异性治疗AD。