INVESTIGATING THE EFFECTS OF MENOPAUSE-INDUCED EPIGENETIC MECHANISMS IN THE BRAIN

研究更年期引起的大脑表观遗传机制的影响

• 批准号: 10388561
• 负责人: Jessica Lee Dennison
• 金额: $ 4.65万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10388561
• 关键词: 3xTg-AD mouse; 4-vinylcyclohexene diepoxide; Acceleration; Acetylation; Affect; Age; Age-Months; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein; Biological Aging; Brain; Characteristics; Chromatin; Cognition; Cognitive; Conflict (Psychology); Critical Pathways; DNA; DNA Methylation; Data; Dementia; Development; Drug Targeting; Enhancers; Enzymes; Epigenetic Process; Estrogen Receptors; Estrogen Replacement Therapy; Estrogens; Event; Female; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Gonadal Steroid Hormones; High Prevalence; Histone Acetylation; Histone Deacetylase; Histones; Hormonal; Hormonal Change; Impaired cognition; Incidence; Injections; Learning; Life; Link; Memory; Memory impairment; Menopause; Metabolic; Metabolic Pathway; Metabolic dysfunction; Metabolism; Mitochondria; Modification; Molecular; Mus; Nerve Degeneration; Neurologic Symptoms; Outcome; Pathogenesis; Pathologic; Pathology; Perimenopause; Persons; Pharmaceutical Preparations; Post-Translational Protein Processing; Postmenopause; Predisposition; Premature Menopause; Premenopause; Prevalence; Progesterone; Protein Analysis; Proteins; Reporting; Research; Technology; Testing; Therapy trial; Transferase; Transgenic Organisms; Woman; abeta deposition; aged; base; behavior test; brain tissue; chromatin modification; chromatin remodeling; cognitive function; design; experience; glucose metabolism; histone modification; human imaging; imaging study; improved; lifetime risk; male; men; mouse model; nano-string; negative affect; novel; object recognition; ovarian failure; personalized therapeutic; promoter; sex; sexual dimorphism; tau Proteins

ABSTRACT More than 100 million people worldwide are estimated to be living with dementia in 2050. Age and sex are the two most important factors determining Alzheimer’s disease (AD) incidence, with women’s lifetime risk double that of men. As women live longer, the total number of women with AD substantially outnumbers men, making the discovery of the molecular links between sex, age, and AD of the greatest significance. One hypothesis for the higher prevalence of AD in women lies in the drastic changes in sex hormones women experience as they traverse menopause, resulting in a depletion of estrogen and progesterone and metabolic changes. Altered metabolism and increased deposition of Amyloid-β begins in peri-menopause and is accompanied by epigenetic modifications, including histone acetylation, which impact on many critical pathways including mitochondrial function. Women also have lower mitochondrial function in brain tissue than males, while new data from our lab demonstrates that sexual dimorphism is observed in cognition and glucose metabolism in an aged AD mouse model. Several reports have made epigenetic modification of histone proteins by histone acetyl transferases (HATs) and histone deacetylases (HDACs) attractive drug targets in AD research. Our lab has shown that HDAC inhibition improves memory in murine models of AD, simultaneously normalizing AD-pathology related molecular changes (e.g. Aβ). To study the sequence of events I propose to utilize a murine model of AD and controlled onset menopause to study epigenetic modifications, metabolism and AD-associated molecular changes that occur during the onset and established ovarian failure. I hypothesize that both histone and non-histone acetyl- group modifications occur during menopause resulting in metabolic dysfunction and acceleration of AD pathology. I will identify acetylation and metabolic changes occurring during peri- and post-menopause-like states in a murine model. These studies will aid in our understanding of the relationship between female sex and AD with the long-term goal to help develop more personalized and/or sex-specific treatments by developing evidence that there is a need for future drug trials to stratify AD patients based on sex.

抽象的 据估计，全世界有超过1亿人在2050年患有痴呆症。年龄和性别是 决定阿尔茨海默氏病（AD）事件的两个最重要的因素，妇女的终生风险双重 那个男人。随着女性寿命的寿命，广告的女性总数远远超过了男性 最大意义的性别，年龄和AD之间的分子联系。一个假设 女性中广告的较高流行率在于性激素女性在她们身上经历的急剧变化 遍历更年期，导致雌激素和孕激素和代谢变化的消耗。改变 代谢和淀粉样蛋白β沉积的增加开始于培育期，并通过表观遗传来完成 修饰，包括组蛋白乙酰化，这会影响包括线粒体在内的许多关键途径 功能。女性在脑组织中的线粒体功能也比男性较低，而我们实验室的新数据 证明在老年AD小鼠的认知和葡萄糖代谢中观察到性二态性 模型。几份报告使组蛋白乙酰转移酶对组蛋白蛋白进行了表观遗传修饰 （帽子）和Hisstone脱乙酰基酶（HDACS）在AD研究中有吸引力的药物靶标。我们的实验室表明HDAC 抑制作用改善了AD鼠模型中的记忆 变化（例如Aβ）。研究事件的顺序，我建议使用AD和受控的鼠模型 开始更年期，研究表观遗传修饰，代谢和与广告相关的分子变化 发生在发病期间并确定的卵巢衰竭。我假设Hisstone和非固定型乙酰基 - 在更年期期间发生组修改，导致代谢功能障碍和AD加速 病理。我将确定在类似于杂期期间和在类似过程中发生的乙酰化和代谢变化 鼠模型中的状态。这些研究将有助于我们理解女性和性别之间的关系 广告具有长期目标，以帮助开发更多个性化和/或性别特定的治疗方法 有证据表明，有必要的药物试验以性别为基础分层AD患者。