Role of circadian clocks in maintaining a healthy nervous system

生物钟在维持神经系统健康中的作用

• 批准号: 8458655
• 负责人: Jadwiga M Giebultowicz
• 金额: $ 3.47万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8458655
• 关键词: Aging; Alzheimer' s Disease; Anabolism; Animals; Antioxidants; Apoptosis; Basic Science; Biochemistry; Biological; Biological Models; Biology; Brain; Brain Pathology; Cells; Circadian Rhythms; Data; Disease; Drosophila genus; Drosophila melanogaster; Enzyme Gene; Enzymes; Feedback; Gene Expression Regulation; Gene Targeting; Genes; Glutamate-Cysteine Ligase; Glutathione; Glutathione Disulfide; Health; Homeostasis; Human; Impairment; Lead; Link; Lipid Peroxides; Lipids; Measures; Medical; Messenger RNA; Molecular; Motor; Nerve Degeneration; Nervous system structure; Neurons; Organism; Oxidation-Reduction; Oxidative Stress; Parkinson Disease; Pathway interactions; Peripheral; Phenotype; Prevention; Proteins; Public Health; Reactive Oxygen Species; Regulation; Research; Risk Factors; Role; Schizophrenia; System; Testing; Time; Tissues; Work; age effect; age related; circadian pacemaker; enzyme biosynthesis; fly; genetic manipulation; improved; innovation; insight; interdisciplinary collaboration; nervous system disorder; normal aging; novel; novel strategies; oxidative damage; prevent; repaired; research study

DESCRIPTION (provided by applicant): The long term objective of this research is to define molecular pathways by which the circadian clock regulates neuronal health. Circadian clocks are molecular feedback loops that generate daily cellular rhythms in the brain and various peripheral tissues. Disruption of the circadian clock has been implicated in neurological disorders but the underling mechanisms connecting the clock to neuronal health are not understood. We have recently shown that loss of the circadian clock in Drosophila dramatically increased accumulation of oxidatively damaged proteins, lipids peroxides, and caused neurodegenerative changes in the brain. Furthermore, we identified a daily rhythm in levels of reactive oxygen species (ROS), while ROS was constantly elevated in flies with a disrupted circadian clock. Molecular oxidative damage is a significant risk factor for age-related neurological disorders and glutathione (GSH) is a key antioxidant that protects neuronal cells against oxidative stress. Depleted GSH levels are found in a number of neurological disorders including schizophrenia, Parkinson's, and Alzheimer's diseases as well as in normal aging. To counteract neurological diseases, basic research is needed to understand mechanisms regulating GSH homeostasis. We obtained exciting preliminary data suggesting that GSH synthesis may be controlled by the circadian clock. We revealed a circadian rhythm in the expression of the catalytic (GCLc) and modulatory (GCLm) subunits of glutamate cysteine ligase (GCL), which is the rate-limiting enzyme in GSH biosynthesis, as well as daily rhythmic changes in GSH levels. These rhythms were abolished in flies with a genetically disrupted circadian clock and in older flies, whose circadian clock becomes impaired. We hypothesize that the circadian clock modulates GSH biosynthesis, and that temporal regulation of GSH homeostasis results in efficient prevention/repair of oxidative damage and protection of the nervous system. To test this hypothesis, we propose an interdisciplinary collaboration using the excellent model system Drosophila melanogaster. In aim 1, we will determine roles of circadian clocks in the regulation of glutathione biosynthesis in the brain. We will then explore functional links between rhythms in GSH biosynthesis and neuronal health in aim 2. Finally, in aim 3 we will determine the effect of an aging circadian clock on the GSH system and neuronal health. Public health significance: Insights obtained from this work may lead to novel strategies to avert neurodegeneration in aging humans, which is a critically important medical and societal issue.

描述（由申请人提供）：这项研究的长期目标是定义昼夜节律调节神经元健康的分子途径。昼夜节律时钟是分子反馈回路，可在大脑和各种外围组织中产生每日细胞节奏。昼夜节律时钟的破坏与神经系统疾病有关，但是将时钟连接到神经元健康的基础机制尚不清楚。我们最近表明，果蝇中昼夜节律的损失大大增加了氧化受损的蛋白质，脂质过氧化物的积累，并在大脑中引起神经退行性变化。此外，我们确定了活性氧（ROS）水平的每日节奏，而ROS则在苍蝇中不断地升高，昼夜节律破裂。分子氧化损伤是与年龄相关的神经系统疾病的重要危险因素，谷胱甘肽（GSH）是保护神经元细胞免受氧化应激的关键抗氧化剂。在许多神经系统疾病中发现了枯竭的GSH水平，包括精神分裂症，帕金森氏症和阿尔茨海默氏病以及正常衰老。为了抵消神经系统疾病，需要基础研究来了解调节GSH稳态的机制。我们获得了令人兴奋的初步数据，表明GSH合成可以由昼夜节律控制。我们揭示了在谷氨酸半胱氨酸结扎酶（GCL）的催化（GCLC）和调节（GCLM）亚基的表达中的昼夜节律，这是GSH生物合成速率限制酶，以及GSH水平的每日节奏变化。这些节奏以遗传破坏的昼夜节律和年龄较大的苍蝇的苍蝇中的苍蝇被消除，昼夜节律受到了损害。我们假设昼夜节律调节GSH的生物合成，并且GSH稳态的时间调节可有效预防/修复神经系统的氧化损伤和保护。为了检验这一假设，我们提出了使用出色的模型系统果蝇Melanogaster提出的跨学科合作。在AIM 1中，我们将确定昼夜节律时钟在大脑中谷胱甘肽生物合成调节中的作用。然后，我们将探索AIM 2中GSH生物合成和神经元健康的节奏之间的功能联系。最后，在AIM 3中，我们将确定圆形时钟对GSH系统和神经元健康的影响。公共卫生的意义：从这项工作中获得的见解可能会导致避免衰老人类神经变性的新策略，这是一个至关重要的医学和社会问题。