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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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病（AD）的主要危险因素，阿尔茨海默病是最常见的痴呆症。数十年来治疗阿尔茨海默病（AD）的临床试验均以失败告终，迫切需要创造性的治疗方法发现新治疗靶点的方法虽然女性的患病率更高，但情况也更严重。神经病理学以及 AD 导致的认知能力下降更大，被诊断患有 AD 的男性进展更快，甚至死亡。然而，人们对性别偏见的驱动机制（无论是激素还是性染色体）知之甚少。我们的长期目标是确定潜在的机制。最近的 GWAS 研究已经确定了基因中的几个 AD 风险位点。由小胶质细胞表达，改变了研究小胶质细胞在 AD 中的潜在致病作用的领域。嗯，小胶质细胞随着衰老和 AD 表现出深刻的表型性别差异。小胶质细胞反应性的差异在机制上有助于性别偏见的疾病进展尽管 AD 的发病与女性绝经过渡相关，但激素替代疗法 (HRT) 产生的结果好坏参半。最近走在 AD 研究的最前沿，特别关注 X 编码的组蛋白修饰剂。本研究的目的是确定性染色体补体（XX v. XY）是否独立于性激素，改变 AD 的病理进展和小胶质细胞激活谱并检验 X 编码的假设赖氨酸特异性去甲基化酶 Kdm6a 有助于小胶质细胞对 AD 的性别分化反应。目标将检验以下假设：（目标 1）性染色体补体改变生存和病理（目标 2）性别染色体调控的差异小胶质细胞对衰老和 AD 的异质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- 通过全基因组、有针对性地去除抑制性 H3K27me3，小胶质细胞对 AD 产生不同的反应。这些研究中产生的配对表型和多组学数据将有助于识别性别差异调节的基因组程序可为两性中的 AD 进展提供保护或风险为了优先考虑小分子或表观基因组编辑的目标，以进行 AD 的治疗干预。该计划具有创新性，因为我们通过性染色体的视角来研究 AD 中的性别差异，并利用突破性的转录组学、表观基因组学和分析技术，获得了以前无法实现的小胶质细胞异质性的解决。