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: 10728343
• 负责人: Jessica Lee Dennison
• 金额: $ 4.75万
• 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/10728343
• 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; Critical Pathways; DNA; DNA Methylation; Data; Dementia; Development; Drug Targeting; EP300 gene; 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; Histone Deacetylase Inhibitor; Histones; Hormonal; Hormonal Change; Impaired cognition; Incidence; Injections; Learning; Life; Life Cycle Stages; 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; 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; neuroprotection; 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.

摘要 据估计，到2050年，全世界将有1亿多人患有痴呆症。年龄和性别是 决定阿尔茨海默病（AD）发病率的两个最重要因素，女性的终生风险增加一倍 那就是男人。随着女性寿命的延长，患有AD的女性总数大大超过男性， 发现性别、年龄和AD之间的分子联系具有重大意义。一个假设是 AD在女性中的较高患病率在于女性经历的性激素的急剧变化， 穿越更年期，导致雌激素和孕激素的消耗和代谢变化。改变 β淀粉样蛋白的代谢和沉积增加开始于围绝经期，并伴有表观遗传 修饰，包括组蛋白乙酰化，影响许多关键途径，包括线粒体 功能女性脑组织中的线粒体功能也低于男性，而我们实验室的新数据显示， 表明在老年AD小鼠中观察到认知和葡萄糖代谢的性二态性 模型已有报道利用组蛋白乙酰基转移酶对组蛋白进行表观遗传修饰 HAT和组蛋白脱乙酰酶（HDAC）是AD研究中有吸引力的药物靶点。我们的实验室已经表明，HDAC 抑制改善AD小鼠模型的记忆，同时使AD病理学相关分子正常化 变化（例如A β）。为了研究事件的顺序，我建议利用AD的小鼠模型和对照组。 绝经期开始，研究表观遗传修饰，代谢和AD相关的分子变化， 发生在发病和建立卵巢衰竭期间。我假设组蛋白和非组蛋白乙酰基- 在绝经期间发生组修改，导致代谢功能障碍和加速AD 病理我将确定乙酰化和代谢变化发生在更年期和绝经后， 在小鼠模型中。这些研究将有助于我们理解女性与男性之间的关系， AD的长期目标是帮助开发更个性化和/或性别特异性的治疗方法， 有证据表明，未来的药物试验需要根据性别对AD患者进行分层。