Cellular mechanisms underlying age-associated changes in sleep and oxidative homeostasis

与年龄相关的睡眠和氧化稳态变化的细胞机制

• 批准号: 10315372
• 负责人: Samantha Jill Tener
• 金额: $ 4.6万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10315372
• 关键词: Acute; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease therapeutic; Animal Model; Animals; Antioxidants; Behavior; Biological Markers; Brain; Cardiovascular Diseases; Cell physiology; Cells; Cessation of life; Data; Defect; Development; Disease; Drosophila genus; Drosophila melanogaster; Dyes; Exhibits; Functional disorder; Genes; Genetic; Genetic Transcription; Goals; Homeostasis; Human; Hyperoxia; Intervention; Longevity; Metabolic Diseases; Modeling; Molecular; Mutation; Organism; Oxidative Phosphorylation; Oxidative Stress; Oxygen; Pathology; Pathway interactions; Pharmacology; Phenotype; Physiological; Play; Predisposition; Reactive Oxygen Species; Resistance; Role; Severity of illness; Sleep; Sleep Disorders; Stress Tests; Testing; Therapeutic; Time; Tissues; Work; age related; biological adaptation to stress; differential expression; disease phenotype; experimental study; fly; genetic manipulation; healthy aging; improved; insight; macromolecule; middle age; mutant; nervous system disorder; neurological pathology; neuropathology; normal aging; normoxia; novel; overexpression; oxidative DNA damage; oxidative damage; protein aggregation; response; sleep pattern; sleep quality; stress state; tool; transcriptome sequencing

Project Summary Sleep is an evolutionarily conserved behavior across the animal kingdom. In both humans and model organisms, a lack of sleep leads to illness and even death. Moreover, in both humans and model organisms, aging leads to changes in sleep patterns and declines in sleep quality. Declining sleep quality is also associated with many age-related diseases, such as Alzheimer’s disease in humans. Therefore, sleep is thought to play an essential role in healthy aging. Age-related diseases are also associated with increased biomarkers of oxidative stress, a state of elevated reactive oxygen species (ROS) and cellular oxidative damage. Using Drosophila melanogaster, the Shirasu-Hiza lab previously showed that sleep promotes defense against oxidative stress. Given these data, my central hypothesis is that sleep acts in specific tissues to activate cellular oxidative stress response pathways and that, as sleep quality declines with age, these oxidative stress defenses weaken and allow age-related pathophysiologies. Because the underlying mechanisms remain unclear, I propose to identify sleep-induced cellular mechanisms that defend against oxidative stress and determine how these change with normal aging and in Alzheimer’s disease models. I will use Drosophila melanogaster, an advantageous model organism for this work because mechanisms underlying both sleep and oxidative stress are conserved from flies to humans and there are established Drosophila models of Alzheimer’s disease. Aim 1 will identify specific tissue(s) in which sleep promotes defense against oxidative stress and determine if these are more vulnerable with age. ROS levels and oxidative damage will be assessed in tissues of young short-sleeping flies relative to controls and compared to middle-aged and old flies. Aim 2 will examine how sleep quality modulates the oxidative stress state and phenotypes of Alzheimer’s disease models. Levels of ROS, oxidative damage, and survival after acute oxidative stress will be used to assess the oxidative stress state of Alzheimer’s model flies with induced or deprived sleep relative to unmanipulated Alzheimer’s disease flies and control. Disease severity will be assessed through lifespan, mobility, and protein aggregation. Aim 3 will investigate specific cellular mechanisms by which sleep promotes defense against oxidative stress and how these change with age. RNA-sequencing will be employed to probe the transcriptional differences between short-sleeping flies and controls under normoxia and hyperoxia, high oxygen treatment. Significantly differentially expressed genes and/or pathways will be assessed for their functional role in sleep-promoted defense against oxidative stress in middle-aged and old flies, as well as Alzheimer’s models. Together, these experiments will determine the cellular connection between sleep and oxidative stress defense and how this relationship changes with age and Alzheimer’s disease pathology. This will improve our understanding of aging, Alzheimer’s disease, and the therapeutic potential of sleep.

项目摘要 睡眠是动物王国中进化保守的行为。在人类和模式生物中， 睡眠不足会导致疾病甚至死亡。此外，在人类和模式生物中，衰老导致 睡眠模式的改变和睡眠质量的下降。睡眠质量下降也与许多 与年龄有关的疾病，如人类的阿尔茨海默病。因此，睡眠被认为是至关重要的 在健康老龄化中的作用糖尿病相关疾病也与氧化应激生物标志物的增加有关， 升高的活性氧（ROS）和细胞氧化损伤的状态。利用果蝇， Shirasu-Hiza实验室先前表明，睡眠可以促进对氧化应激的防御。根据这些数据， 我的中心假设是睡眠在特定组织中起作用，激活细胞氧化应激反应途径 而且，随着睡眠质量随着年龄的增长而下降，这些氧化应激防御能力减弱，并允许与年龄相关的 病理生理学由于潜在的机制尚不清楚，我建议确定睡眠诱导的 防御氧化应激的细胞机制，并决定这些机制如何随着正常衰老而变化 和阿尔茨海默病模型中的作用。我将使用果蝇，一种有利的模式生物， 这是因为睡眠和氧化应激的潜在机制从苍蝇到人类都是保守的 并且已经有了阿尔茨海默病的果蝇模型。目标1将识别特定组织， 睡眠促进对氧化应激的防御，并确定这些是否随着年龄的增长而变得更加脆弱。ROS 相对于对照，将在年轻的短睡眠果蝇的组织中评估水平和氧化损伤， 与中年和老年苍蝇相比。目标2将研究睡眠质量如何调节氧化应激状态 和阿尔茨海默病模型的表型。ROS水平，氧化损伤和急性 氧化应激将用于评估阿尔茨海默病模型果蝇的氧化应激状态， 剥夺睡眠相对于未经处理的阿尔茨海默病苍蝇和控制。将评估疾病严重程度 通过寿命、移动性和蛋白质聚集。目的3将研究特定的细胞机制， 睡眠促进对氧化应激的防御，以及这些如何随着年龄的变化。RNA测序将是 用于探测短睡眠果蝇和常氧对照之间的转录差异， 高氧，高氧治疗。将评估显著差异表达的基因和/或途径 在中老年果蝇中，它们在促进睡眠防御氧化应激方面的功能作用， 老年痴呆症的模型。总之，这些实验将确定睡眠和睡眠之间的细胞联系。 氧化应激防御以及这种关系如何随着年龄和阿尔茨海默病病理学的变化而变化。这 将提高我们对衰老、阿尔茨海默病和睡眠治疗潜力的理解。