Epigenetic Signaling in the Aging Hypothalamus

衰老下丘脑的表观遗传信号

• 批准号: 10227244
• 负责人: Alejandro Lomniczi
• 金额: $ 21.88万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227244
• 关键词: 20 year old; Acute; Adrenal Glands; Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Animal Model; Animals; Archives; Blood Circulation; Body fat; Brain; Circadian Rhythms; Clinical; Clinical Research; Clinical Trials; Cognitive; DNA Methylation; DNA methylation profiling; Data; Detection; Development; Diet; Disease; Elderly; Environment; Epigenetic Process; Estradiol; Estrogen Replacement Therapy; Estrogens; Excision; Exploratory/Developmental Grant; Exposure to; Fatty acid glycerol esters; Female; Foundations; Funding; Gene Expression; Gene-Modified; Genes; Goals; Gonadal Steroid Hormones; Hormonal; Hormonal Change; Hormone replacement therapy; Hypothalamic structure; Immune response; Impaired cognition; Individual; Inferior; Inflammation; Lead; Light; Macaca mulatta; Maintenance; Memory; Menopause; Menstrual cycle; Methylation; Modification; Molecular; Monkeys; Neuraxis; Neurosecretory Systems; Operative Surgical Procedures; Output; Ovarian; Ovary; Overweight; Pathology; Pathway interactions; Pattern; Physiological; Play; Positioning Attribute; Postmenopause; Prevention; Primates; RNA; Resolution; Rest; Sampling; Signal Transduction; Site; Sleep; Sleep Wake Cycle; Sleep disturbances; Symptoms; System; Testing; United States National Institutes of Health; Woman; Women' s Health; age related; attenuation; base; brain tissue; circadian; circadian pacemaker; cognitive benefits; cognitive performance; epigenetic profiling; experience; genome-wide; glucose metabolism; healthy aging; human model; improved; in vivo; insight; insulin sensitivity; mRNA Expression; neuropathology; neurotransmission; nonhuman primate; novel; sleep quality; spatial memory; sugar; suprachiasmatic nucleus; synaptic function; targeted treatment; transcriptome sequencing; translational model; western diet; young adult

PROJECT SUMMARY In women, aging is characterized by a marked decrease in circulating estrogen (E) levels, which negatively impacts many physiological systems including sleep-wake cycles and cognitive performance. Consequently, many postmenopausal women chose to undergo E hormone replacement therapy (HRT), with the hope of reversing or alleviating these negative symptoms. Unfortunately, the underlying neuroendocrine mechanisms associated with HRT are poorly understood and the long-term efficacy of these hormonal manipulations on the central nervous system are unclear, especially in women who are overweight. Using the rhesus macaque as a translational animal model, we previously demonstrated an age-associated increase in perturbed sleep-wake cycles, and found that individuals with the most perturbed cycles showed inferior cognitive performance in a spatial memory task, as well as compromised immune responses. We also demonstrated cognitive benefits resulting from long-term administration of E to old ovariectomized females; importantly, however, the beneficial effects of E on various physiological functions were not sustained in animals maintained on a high-fat, high- sugar Western-style diet (WSD). The goal of this R21 exploratory study is to test the hypothesis that age- related molecular changes within the suprachiasmatic nucleus (SCN) contribute to disrupted sleep-wake cycles and that these are exacerbated by the marked postmenopausal attenuation of circulating E concentrations, especially when concomitantly exposed to a WSD. Therefore, our study will examine DNA methylation developments within the SCN (Aim 1), and use RNA-seq to profile gene expression changes (Aim 2), using archived brain tissue from the following pair-groups of previously-characterized rhesus macaques: 1. Young adult ovary-intact females (on a standard diet) 2. Old ovary-intact females (on a standard diet) 3. Old ovariectomized females (on a standard diet) 4. Old ovariectomized females (on a standard diet + treated with HRT for ~3 years) 5. Old ovariectomized females (on a WSD for ~3 years) 6. Old ovariectomized females (on a WSD for ~3 years + treated with HRT for ~3 years) Using a previously-validated MethylSeq approach to provide single-base resolution DNA methylation data, we will examine differential methylation CpG (DMC) and region (DMR) in the SCN – i.e., the well-established site of the master circadian clock that plays a key role in sleep maintenance and synchronizing daily physiological functions. We predict that aging, maintenance on a WSD, and insufficient E in the circulation produce functional epigenetic modifications within the core clock mechanism of the SCN that result in perturbed circadian activity-rest pattern, and in turn predispose individuals to development of Alzheimer’s disease.

项目摘要 在女性中，衰老的特征是循环雌激素（E）水平显著下降， 影响许多生理系统，包括睡眠-觉醒周期和认知表现。因此，委员会认为， 许多绝经后妇女选择接受E激素替代疗法（HRT），希望 缓解或缓解这些不良症状。不幸的是，潜在的神经内分泌机制 与HRT相关的激素缺乏了解，这些激素操作对 中枢神经系统不清楚，特别是超重的女性。利用恒河猴作为 翻译的动物模型，我们以前证明了年龄相关的增加扰动睡眠-觉醒 周期，并发现最受干扰的周期的个体在一个特定的时间内表现出较差的认知表现。 空间记忆任务，以及受损的免疫反应。我们还证明了认知方面的好处 由于长期给予E的老年卵巢切除女性;重要的是，然而，有益的 E对各种生理功能的影响在维持在高脂肪、高脂、高蛋白水平的动物中并不持续。 糖西式饮食（WSD）。这项R21探索性研究的目的是检验年龄- 视交叉上核（SCN）内的相关分子变化导致睡眠-觉醒周期中断 并且这些症状由于绝经后循环E浓度的显著衰减而加重， 特别是当同时暴露于WSD时。因此，我们的研究将检查DNA甲基化 SCN内的发展（目标1），并使用RNA-seq分析基因表达变化（目标2），使用 来自以下先前表征的成对组恒河猴的存档脑组织： 1.卵巢完整的年轻成年雌性（标准饮食） 2.卵巢完整的老年雌性（标准饮食） 3.切除卵巢的老年雌性动物（标准饮食） 4.切除卵巢的老年雌性动物（标准饮食+HRT治疗约3年） 5.切除卵巢的老年雌性（接受WSD约3年） 6.卵巢切除的老年女性（接受WSD治疗约3年+接受HRT治疗约3年） 使用先前验证的MethylSeq方法提供单碱基分辨率DNA甲基化数据，我们 将检查SCN中的差异甲基化CpG（DMC）和区域（DMR）-即，完善的网站 主生物钟在睡眠维持和同步日常生理方面发挥着关键作用 功能协调发展的我们预测，老化，维护的一个水务署，并在流通中的不足E产生 SCN的核心时钟机制内的功能性表观遗传修饰， 昼夜活动-休息模式，并反过来使个体易患阿尔茨海默病。