Microglial Activation and Inflammatory Endophenotypes Underlying Sex Differences of Alzheimer’s Disease

阿尔茨海默病性别差异背后的小胶质细胞激活和炎症内表型

基本信息

批准号：
10755779
负责人：
Feixiong Cheng
金额：
$ 55.82万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-22 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10755779
关键词：
ATAC-seq Address Adult Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk American Architecture Basic Science Biological Assay Blood Brain CX3CL1 gene Cause of Death Cell Nucleus Cells Clinical Research Cognitive Data Data Analyses Dementia Development Diagnosis Disease Disease Progression Enhancers Epigenetic Process Evaluation Female Foundations Freezing Funding Future Gene Expression Genes Genetic Genetic Transcription Genomics Goals Heterogeneity Human IL7 gene Immune Immune system Immunology Immunomodulators Incidence Individual Infiltration Inflammation Inflammatory Interleukin-6 Interleukin-9 Machine Learning Mediating Microglia Molecular Morbidity - disease rate Myeloid-derived suppressor cells National Institute on Aging Network-based Neuroglia Neuroimmune Outcome Pathogenesis Peripheral Peripheral Blood Mononuclear Cell Persons Phenotype Plasma Play Population Heterogeneity Predisposition Prevalence Preventive Prognosis Reporting Research Role Sampling Sex Differences System Systems Biology Technology Testing Therapeutic Transforming Growth Factor alpha United States Variant Woman brain tissue care costs cell type chemokine clinical development clinically actionable clinically relevant cohort cost cytokine differential expression endophenotype epidemiology study epigenome epigenomics functional genomics gene regulatory network genetic signature genomic data genomic locus glial activation human data human interactome human subject improved individualized medicine innovation insight male men mild cognitive impairment molecular targeted therapies mortality multimodality nervous system disorder neuropathology next generation novel novel therapeutics overexpression precision medicine prenatal prevent promoter protein expression sex sexual dimorphism single cell analysis single nucleus RNA-sequencing symptomatic improvement systemic inflammatory response therapeutic development therapy development transcription factor transcriptome transcriptome sequencing transcriptomics translational study treatment response

项目摘要

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 neuro and systemic inflammation and sex differences remains understudied. Our preliminary single-nucleus genomic analyses have identified sex-specific microglial gene signatures in AD patient brains. Single-cell transcriptomic data analysis of human peripheral blood mononuclear cells (PBMCs) implies that multiple sex-specific, candidate pro-inflammatory genes highly overexpressed in myeloid-derived suppressor cells (MDSCs) and other immune cell types in AD. We therefore posit that an interplay between microglia and systematic inflammatory mechanisms (termed the “Microglial activation and inflammatory endophenotypes”) exists and that understanding this system will be essential to improve the mechanistic elucidation of AD pathogenesis and therapeutic development in a sex-specific manner. Recent advances of multimodal single-cell genomic and epigenomic analyses have shed insights into 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 AD genetic loci and functional genomic data from existing diverse AD cohorts 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 treatment development in both 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 National Institute of Aging (NIA)-funded Alzheimer's Disease Research Centers (ADRCs). Aim 1 will test the hypothesis that microglial activation and central neuro-immune transcriptional networks mediate sex differences in AD using single-nucleus genomic (snRNA-seq) and epigenomic (snATAC-seq) analyses of human frozen brain tissues. In parallel, we will utilize network-based, integrative analyses of snRNA-seq and snATAC-seq data from human frozen brains and large-scale genetic and functional genomic data from existing AD cohorts with diverse population to identify glial cell type-specific promoters and enhancers that encode sex-specific master gene regulatory networks for AD. Aim 2 will test the hypothesis that cell type-specific peripheral immune signatures and interactome network changes in AD pathogenesis and progression act in a sex-specific manner. In summary, our project will identify clinically actionable immune molecular mechanisms underlying sex differences in AD pathobiology from the central neuro-immune and peripheral immune systems. The successful completion of this project will advance the understanding of sex difference in AD and serve as the foundation for future translational studies to inform the development of precision medicine in a sex-specific manner.

项目概要阿尔茨海默病（AD）在患病率、发病率、症状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。据报道，对炎症和 AD 进展的易感性，神经和神经之间的关系我们的初步单核基因组仍在研究中。分析已经确定了 AD 患者大脑中性别特异性的小胶质细胞基因特征。人外周血单核细胞 (PBMC) 的数据分析表明，多种性别特异性、候选促炎基因在骨髓源性抑制细胞 (MDSC) 和其他免疫细胞中高度过度表达因此，我们假设小胶质细胞和系统性炎症之间存在相互作用。机制（称为“小胶质细胞激活和炎症内表型”）是存在的，并且了解这个系统对于改善 AD 发病机制的机制阐明和多模式单细胞基因组和性别特异性治疗的最新进展。表观基因组分析有助于全面了解神经免疫和 AD 中性别差异的外周免疫系统整合。表观基因组（人类相互作用组）以及大规模 AD 遗传位点和功能基因组数据现有的多样化 AD 群体对于这种识别至关重要。为了解决这一假设，我们的短期目标是。是寻找针对 AD 性别差异的下一代免疫调节剂和分子靶向治疗我们将利用大规模单细胞基因组和 AD 患者的发展。从具有不同程度 AD 病理学的人类大脑和血液生成的表观基因组数据可在我们的国家老龄化研究所 (NIA) 资助的阿尔茨海默病研究中心 (ADRC) 将测试 Aim 1。小胶质细胞激活和中枢神经免疫转录网络介导性别差异的假设使用人类冷冻的单核基因组 (snRNA-seq) 和表观基因组 (snATAC-seq) 分析来治疗 AD 与此同时，我们将利用基于网络的 snRNA-seq 和 snATAC-seq 数据综合分析。来自人类冷冻大脑和现有 AD 队列的大规模遗传和功能基因组数据不同群体来鉴定编码性别特异性主序列的神经胶质细胞类型特异性启动子和增强子目标 2 将检验细胞类型特异性外周免疫的假设。 AD 发病机制和进展中的特征和相互作用组网络变化以性别特异性方式起作用。总之，我们的项目将确定临床上可操作的性行为背后的免疫分子机制 AD病理学与中枢神经免疫系统和外周免疫系统的差异。该项目的完成将增进对 AD 性别差异的理解，并为未来的转化研究将以特定性别的方式为精准医学的发展提供信息。