Epigenetic Signaling in the Aging Hypothalamus

衰老下丘脑的表观遗传信号

基本信息

批准号：
10056001
负责人：
Alejandro Lomniczi
金额：
$ 26.25万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10056001
关键词：
20 year old Acute Adrenal Glands Adult Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease pathology Animal Model Animals Archives Blood Circulation Body fat Brain Circadian Rhythms Clinical Clinical Research Clinical Trials Cognitive DNA Methylation 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&apos 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 young adult

项目摘要

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.

项目概要对于女性来说，衰老的特点是循环雌激素 (E) 水平显着下降，这对女性健康产生负面影响。影响许多生理系统，包括睡眠-觉醒周期和认知能力测试，许多绝经后妇女选择接受激素替代疗法（HRT），希望不幸的是，逆转或减轻这些负面症状的潜在神经内分泌机制。人们对与 HRT 相关的激素知之甚少，并且这些激素操作对激素的长期疗效中枢神经系统尚不清楚，特别是对于超重的女性来说，恒河猴作为神经系统。在转化动物模型中，我们之前证明了睡眠-觉醒紊乱与年龄相关的增加周期，并发现周期扰动最严重的个体在我们还证明了空间记忆任务以及免疫反应受损的认知益处。然而，重要的是，对老年切除卵巢的女性长期服用 E 会产生有益的效果；在维持高脂肪、高营养的动物中，E 对各种生理功能的影响并未持续。糖西式饮食 (WSD) 这项 R21 探索性研究的目标是检验年龄-糖饮食的假设。视交叉上核（SCN）内的相关分子变化导致睡眠-觉醒周期紊乱而且绝经后循环 E 浓度显着减弱会加剧这些情况，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 来分析基因表达变化（目标 2），使用存档的脑组织来自以下两对先前鉴定的恒河猴： 1. 卵巢完整的年轻成年雌性（标准饮食） 2.卵巢完整的高龄雌性（标准饮食） 3.老年切除卵巢女性（标准饮食） 4.老年切除卵巢女性（标准饮食+HRT治疗约3年） 5. 已切除卵巢的老年女性（使用 WSD 约 3 年） 6. 老年卵巢切除女性（WSD 约 3 年 + HRT 治疗约 3 年）使用先前验证的 MmethylSeq 方法来提供单碱基分辨率 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) – 即已建立的位点主生物钟的存在，在睡眠维持和同步日常生理方面发挥着关键作用我们预测，老化、WSD 维护和循环中 E 不足会产生影响。 SCN 核心时钟机制内的功能性表观遗传修饰会导致扰动昼夜节律活动-休息模式，进而使个体易患阿尔茨海默病。