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。生物钟是分子反馈回路，在大脑和各种外周组织中产生每日细胞节律。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潜在机制尚不清楚。我们最近的研究表明，果蝇生物钟的丢失会显著增加氧化损伤蛋白质、脂质过氧化物的积累，并导致大脑神经退行性变化。此外，我们确定了活性氧（ROS）水平的每日节律，而ROS在昼夜节律钟中断的果蝇中不断升高。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，谷胱甘肽（GSH）是保护神经细胞免受氧化应激的关键抗氧化剂。在许多神经系统疾病，包括精神分裂症，帕金森氏症和阿尔茨海默氏症以及正常衰老中发现GSH水平耗尽。为了对抗神经系统疾病，需要进行基础研究以了解GSH稳态调节机制。我们获得了令人兴奋的初步数据表明，GSH的合成可能是由生物钟控制。我们揭示了一个昼夜节律的催化（GCLc）和调节（GCLm）的谷氨酸半胱氨酸连接酶（GCL），这是在GSH生物合成的限速酶，以及每天的节奏变化的亚基的表达GSH水平。这些节奏被废除的苍蝇与基因干扰的昼夜节律钟和老年苍蝇，其昼夜节律变得受损。我们推测，昼夜节律钟调节GSH的生物合成，以及GSH稳态的时间调节导致氧化损伤的有效预防/修复和神经系统的保护。为了验证这一假设，我们提出了一个跨学科的合作，使用优秀的模型系统果蝇。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，我们将探讨目标2中GSH生物合成节律和神经元健康之间的功能联系。最后，在目标3中，我们将确定衰老的生物钟对GSH系统和神经元健康的影响。公共卫生意义：从这项工作中获得的见解可能会导致新的策略，以避免老年人的神经退行性变，这是一个至关重要的医学和社会问题。 公共卫生相关性：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潜在机制尚不清楚。拟议的研究将确定生物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中被耗尽，包括精神分裂症，帕金森氏症和阿尔茨海默氏症。从这项工作中获得的见解可能会导致新的策略，以避免老年人的神经退行性变，这是一个至关重要的医学和社会问题。