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: 10704130
• 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/10704130
• 关键词: 3xTg-AD mouse; AD transgenic mice; APP-PS1; Address; Age; Aging; Agreement; 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; Creativeness; 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; Gliosis; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Grant; Heterogeneity; Hippocampus; Hispanic; Histones; Hormonal; Hormone replacement therapy; Human; Immune response; Impaired cognition; Inflammatory; Institution; Intervention; Knowledge; Leadership; Lysine; Macrophage; Manuscripts; Mathematics; Medical Research; Mentors; Microglia; Molecular; Morphology; Multiomic Data; Mus; National Research Service Awards; Neurofibrillary Tangles; Neurosciences; Oklahoma; Outcome; Ovary; Paper; Pathologic; Pathology; Pathway interactions; Perimenopause; 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; glial activation; graduate student; histone modification; human disease; immunological diversity; innovation; lens; 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.

摘要 性别和年龄是阿尔茨海默病(AD)的主要危险因素，AD是最常见的痴呆症形式。之后 几十年来治疗阿尔茨海默病(AD)的临床试验失败了，迫切需要创造性的治疗 发现新的治疗靶点的方法。而女性的患病率更高，更严重 神经病理学，以及AD患者认知能力的下降，被诊断为AD的男性进展到死亡的速度更快。 然而，人们对驱动性别偏见的机制(无论是荷尔蒙还是性染色体)知之甚少。 脑老化对AD病理的反应。我们的长期目标是确定潜在的机制 管理对AD的性别偏见反应。最近的GWAS研究已经在基因中发现了几个AD风险基因 仅由小胶质细胞表达，转移了研究领域，以探索小胶质细胞在AD中的潜在致病作用。AS 小胶质细胞在衰老和阿尔茨海默病中表现出明显的表型性别差异。我们假设性行为 小胶质细胞反应性的差异在机制上促进了性别偏见疾病的进展 广告。尽管阿尔茨海默病的发病与女性的绝经过渡有关，但激素替代疗法 (HRT)产生了好坏参半的结果。以前被低估的性染色体贡献的作用 最近在AD研究中走在了前列，特别强调X编码的组蛋白修饰物。这个 本研究的目的是确定性染色体补体(XX v.XY)是否不依赖于性激素， 改变AD的病理进展和小胶质细胞激活特征，并检验X编码的假说 赖氨酸特异的脱甲基酶Kdm6a有助于AD的性分化小胶质细胞反应。我们的特定 AIMS将检验以下假设：(AIMS 1)性染色体互补改变生存和病理 阿尔茨海默病的进展(斑块/缠结，小胶质细胞增多症)；(目标2)性别染色体调控的差异 异质小胶质细胞对衰老和阿尔茨海默病的反应部分是由组蛋白的改变驱动的 修饰(H3K27me3)；(目标3)小胶质细胞X编码的Kdm6a表达足以引起性行为- 通过全基因组、靶向移除抑制性H3K27me3，对阿尔茨海默病的不同小胶质细胞反应。这个 这些研究中产生的表型和多染色体配对数据将有助于性别鉴定-- 不同调控的基因组程序，为AD的进展提供保护或风险 以便优先考虑小分子或表观基因组编辑的靶点，以进行AD的治疗干预。这项研究 PLAN是创新的，因为我们通过性染色体的透镜研究AD的性别差异，并利用 突破性的转录学、表观基因组学和分析技术，以获得以前无法实现的 小胶质细胞异质性的分辨率。