Sex chromosomal regulation of hippocampal microglial activation with Alzheimer's disease and aging

海马小胶质细胞激活的性染色体调控与阿尔茨海默病和衰老

• 批准号: 10481271
• 负责人: Sarah Renee Ocanas
• 金额: $ 43.7万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-13 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10481271
• 关键词: 3xTg-AD mouse; AD transgenic mice; APP-PS1; Address; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; American; Area; Automobile Driving; Award; Border Community; Brain; Calculi; Cell surface; Cessation of life; Clinical Treatment; Clinical Trials; Cognition; Data; Dementia; Development; Diagnosis; Disease; Disease Progression; Doctor of Philosophy; Educational process of instructing; Environment; Excision; Faculty Recruitment; Female; Foundations; Four Core Genotypes; Funding; Genes; Genetic Transcription; Genomics; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Grant; Heterogeneity; Hippocampus (Brain); Hispanic; Histones; Hormonal; Hormone replacement therapy; Human; Immune response; Impaired cognition; Inflammatory; Institution; Intervention; Knowledge; Leadership; Life; Light; Lysine; Manuscripts; Mathematics; Medical Research; Menopause; Mentors; Microglia; Molecular; Morphology; Multiomic Data; Mus; National Research Service Awards; Neurofibrillary Tangles; Neurosciences; Oklahoma; Outcome; Ovary; Paper; Pathologic; Pathology; Pathway interactions; Phagocytes; Phenotype; Phenotypic Sex; Ploidies; Positioning Attribute; Prevalence; Principal Investigator; Process; Regulation; Research; Research Personnel; Resolution; Risk; Role; Science; Sex Bias; Sex Chromosomes; Sex Differences; South Texas; Stimulus; Techniques; Testing; Testis; Therapeutic Intervention; Time; United States National Institutes of Health; Woman; Work; X Chromosome; aging brain; biological sex; biological systems; career; cell type; computing resources; data integration; disabling symptom; epigenome; epigenome editing; epigenomics; experience; experimental study; genome wide association study; genome-wide; genotypic sex; graduate student; histone modification; human disease; immunological diversity; innovation; lens; macrophage; male; meetings; men; mouse model; neuropathology; new therapeutic target; novel; phenotypic data; programs; protective factors; response; risk variant; sex; small molecule; symposium; therapeutic target; transcriptomics

ABSTRACT Sex and age are the primary risk factors for Alzheimer’s disease (AD), the most common form of dementia. After decades of failed clinical trials for the treatment of Alzheimer’s disease (AD), there is an urgent need for creative approaches to uncover new therapeutic targets. While women experience a greater prevalence, more severe neuropathology, and greater cognitive decline with AD, men diagnosed with AD progress more quickly to death. However, little is known about the mechanisms (whether hormonal or sex chromosomal) driving the sex-biased response to AD pathology with brain aging. Our long-term goal is to identify the underlying mechanisms governing the sex-biased response to AD. Recent GWAS studies have identified several AD risk loci in genes exclusively expressed by microglia, shifting the field to explore potential causative roles of microglia in AD. As well, microglia show profound phenotypic sex differences with aging and AD. We hypothesize that sex differences in microglial responsivity contribute mechanistically to the sex-biased disease progression seen in AD. Although the onset of AD correlates to the menopausal transition in women, hormone replacement therapies (HRT) have generated mixed results. The formerly under-appreciated role of sex chromosomal contributions has recently come to the forefront in AD research, with a special emphasis on X-encoded histone modifiers. The objective of this study is to determine if sex chromosome complement (XX v. XY), independent of sex hormones, alters pathological progression and microglial activational profiles in AD and test the hypothesis that X-encoded lysine-specific demethylase Kdm6a contributes to the sexually divergent microglial response to AD. Our specific aims will test the following hypotheses: (Aim 1) sex chromosome complement alters survival and pathological progression (plaques/tangles, microgliosis) of AD; (Aim 2) sex chromosomally regulated differences in heterogeneous microglial cell responses to aging and AD are driven, in part, by alterations in histone modifications (H3K27me3); (Aim 3) microglial X-encoded Kdm6a expression is sufficient to cause sexually- divergent microglial response to AD through genome-wide, targeted removal of repressive H3K27me3. The paired phenotypic and multi-omic data generated in these studies will facilitate the identification of sex- differentially regulated genomic programs that confer protection or risk to the progression of AD in both sexes in order to prioritize targets for small molecule or epigenome editing for therapeutic intervention in AD. The research plan is innovative because we investigate sex differences in AD through the lens of sex chromosomes and utilize ground-breaking transcriptomic, epigenomic, and analytical techniques to gain a previously unattainable resolution of microglia heterogeneity.

抽象的 性别和年龄是阿尔茨海默氏病（AD）的主要危险因素，这是最常见的痴呆症形式。后 几十年来治疗阿尔茨海默氏病（AD）的临床试验失败，迫切需要创意 发现新的治疗靶标的方法。虽然女性的患病率更高，但更严重 神经病理学和随着AD的认知能力越来越大，被诊断为AD的男性更快地进展到死亡。 但是，关于驱动性偏见的机制（无论是马染色体还是性别染色体）知之甚少 对AD病理学的反应随着脑衰老。我们的长期目标是确定基本机制 管理对广告的性别偏见的反应。最近的GWAS研究已经确定了基因中的几个AD风险基因座 由小胶质细胞独家表达，转移了该领域，以探索小胶质细胞在AD中的潜在致病作用。作为 好吧，小胶质细胞在衰老和AD中表现出深远的表型性别差异。我们假设性别 小胶质反应性的差异在机械上有助于性偏见的疾病进展 尽管AD的发作与女性的更年期过渡相关，但马龙替代疗法 （HRT）产生了混合的结果。以前的性染色体贡献的作用不足。 最近，在广告研究中走到了最前沿，特别强调了X编码的组蛋白修饰符。这 这项研究的目的是确定性别染色体完成（xxv。xy），独立于性恐怖剂， 改变AD中的病理进展和小胶质细胞活化谱，并测试X编码的假设 赖氨酸特异性脱甲基酶KDM6A有助于对AD的性发散小胶质反应。我们的具体 目标将检验以下假设：（目标1）性染色体完成会改变生存和病理 AD的进展（斑块/缠结，小胶质细胞增多）； （AIM 2）性染色体调节的差异 异构小胶质细胞对衰老和AD的反应部分是由于组蛋白的改变而驱动的 修改（H3K27me3）; （AIM 3）小胶质X编码的KDM6A表达足以引起性 - 通过全基因组对AD的发散小胶质响应，靶向去除反射性H3K27me3。这 这些研究中产生的成对的表型和多摩变数据将有助于鉴定性别 受到差异调节的基因组计划，以保护或风险在两个性别中的AD进展 为了确定针对AD治疗干预的小分子或表观基因组编辑的靶标。研究 计划具有创新性，因为我们通过性别染色体的镜头研究AD的性别差异并利用 开创性的转录组，表观基因组和分析技术，以获得以前无法实现的 小胶质细胞异质性的分辨率。