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.

摘要