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: 8176952
• 负责人: Jadwiga M Giebultowicz
• 金额: $ 23.08万
• 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/8176952
• 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. PUBLIC HEALTH RELEVANCE: Disruption of the biological (circadian) clock has been implicated in neurological disorders but the underling mechanisms connecting the clock to neuronal health are not understood. The proposed studies will determine how the clock regulates biosynthesis of glutathione, a key antioxidant that is depleted in many neurological disorders including schizophrenia, Parkinson's, and Alzheimer's diseases. 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）：本研究的长期目标是确定生物钟调节神经元健康的分子途径。昼夜节律钟是分子反馈回路，可在大脑和各种外周组织中产生日常细胞节律。生物钟的破坏与神经系统疾病有关，但将生物钟与神经元健康联系起来的基本机制尚不清楚。我们最近发现，果蝇生物钟的丧失会显着增加氧化损伤蛋白质、脂质过氧化物的积累，并引起大脑的神经退行性变化。此外，我们还发现了活性氧（ROS）水平的每日节律，而在生物钟被破坏的果蝇中，ROS 不断升高。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，而谷胱甘肽 (GSH) 是保护神经元细胞免受氧化应激的关键抗氧化剂。谷胱甘肽水平降低存在于许多神经系统疾病中，包括精神分裂症、帕金森病和阿尔茨海默病以及正常衰老过程。为了对抗神经系统疾病，需要进行基础研究来了解 GSH 稳态的调节机制。我们获得了令人兴奋的初步数据，表明 GSH 合成可能受生物钟控制。我们揭示了谷氨酸半胱氨酸连接酶 (GCL) 的催化 (GCLc) 和调节 (GCLm) 亚基（GCL 是 GSH 生物合成中的限速酶）表达的昼夜节律，以及 GSH 水平的每日节律变化。在生物钟基因被破坏的果蝇和生物钟受损的老年果蝇中，这些节律被废除。我们假设生物钟调节 GSH 生物合成，并且 GSH 稳态的时间调节可有效预防/修复氧化损伤并保护神经系统。为了检验这一假设，我们提出使用优秀的模型系统果蝇进行跨学科合作。在目标 1 中，我们将确定生物钟在大脑谷胱甘肽生物合成调节中的作用。然后，我们将在目标 2 中探索 GSH 生物合成节律与神经元健康之间的功能联系。最后，在目标 3 中，我们将确定衰老生物钟对 GSH 系统和神经元健康的影响。公共健康意义：从这项工作中获得的见解可能会带来避免老年人神经退行性疾病的新策略，这是一个至关重要的医学和社会问题。 公共健康相关性：生物（昼夜节律）时钟的破坏与神经系统疾病有关，但将生物钟与神经元健康联系起来的基本机制尚不清楚。拟议的研究将确定时钟如何调节谷胱甘肽的生物合成，谷胱甘肽是一种关键的抗氧化剂，在许多神经系统疾病（包括精神分裂症、帕金森病和阿尔茨海默病）中都会被耗尽。从这项工作中获得的见解可能会带来避免老年人神经退行性变的新策略，这是一个至关重要的医学和社会问题。