Non-transcriptional regulation of circadian physiology

昼夜节律生理学的非转录调节

• 批准号: 10835328
• 负责人: JOANNA Chungyen CHIU
• 金额: $ 13.7万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-11 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10835328
• 关键词: Animal Model; Animals; Behavior; Behavioral; Biochemical; Biological Assay; Biological Rhythm; Biology; Biotin; Brain; Bypass; Cell physiology; Cells; Chronic Disease; Circadian Dysregulation; Circadian Rhythms; Collaborations; Cues; Cysteine; Diet; Drosophila genus; Eating; Elements; Environment; Equilibrium; Exhibits; Fasting; Future; Gene Expression; Genetic; Genetic Transcription; Goals; High Fat Diet; Homeostasis; Hour; Human; Immune System Diseases; Knowledge; Life Style; Light; Link; Lipids; Liver; Maintenance; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Membrane; Metabolic; Metabolic Diseases; Metabolism; Modeling; Modernization; Modification; Molecular; Molecular Biology; Mus; Nutrient; Nutritional; Organ; Output; Palmitates; Pathology; Periodicity; Peripheral; Phase; Phosphorylation; Physiological; Physiology; Play; Post-Translational Protein Processing; Process; Protein S; Proteins; Proteome; Proteomics; Publishing; Regulation; Regulatory Pathway; Reporting; Role; Saturated Fatty Acids; Schedule; Signal Transduction; Site; Sleep Wake Cycle; Stress; Technology; Temperature; Testing; Time; Time-restricted feeding; Tissues; Western Blotting; Work; blood-brain barrier permeabilization; circadian; circadian pacemaker; circadian regulation; circadian transcriptome; feeding; fly; healthspan; human disease; insight; lipid metabolism; lipidomics; model organism; mouse model; nervous system disorder; new therapeutic target; nutrition; palmitoylation; programs; protein function; protein protein interaction; receptor; response; sugar; transcription factor

PROJECT SUMMARY Robust daily biological rhythms are key hallmarks of animal healthspan and are strongly regulated by circadian clocks. These cell-autonomous molecular timers enable animals to adapt to predictable daily changes in their environment. Clock-controlled outputs are all-encompassing and clock disruption is associated with a wide range of pathologies and chronic diseases. In the natural world, environmental signals, e.g. light and temperature, enable animal circadian clocks to control timing of food intake. Nutrient influx can therefore provide metabolic signals to reinforce environmental signals, promoting synchrony in cellular physiology to balance metabolism and energy use. Efforts to understand the underpinnings of circadian clocks and their control over daily biological rhythms have long focused on regulation at the transcriptional level, as core oscillator proteins are transcription factors that collaborate to govern rhythmic expression of genes involved in diverse cellular processes. More recent studies have uncovered complementary non- transcriptional mechanisms, including protein post-translational modifications (PTMs), that are critical for robust daily rhythms. The overall goal of this project is to advance our understanding of the role of nutrient-dependent PTMs in mediating metabolic regulation of time-of-day-specific protein functions to orchestrate daily biological rhythms. We will use the diurnal Drosophila model to test the central hypothesis that metabolic signals from clock-controlled feeding activity and cellular metabolism regulate rhythmic S-palmitoylation of cellular proteins, and S-palmitoylation is necessary for maintenance of robust daily biological rhythms. S-palmitoylation is the only reversible lipid PTM; it is the attachment of palmitate, a saturated fatty acid, to cysteines. S- palmitoylation targets a wide range of proteins from transcription factors to membrane receptors, and is known to alter their stability, activity, localization, and protein-protein interactions. The specific aims of this project are to investigate the mechanisms by which clock-dependent metabolic signals regulate S-palmitoylation rhythms and how these rhythms are impacted by nutritional stress (Aim 1); to identify proteins that exhibit daily rhythms in S-palmitoylation (Aim 2); and to determine if palmitoylation regulates daily biology rhythms (Aim 3). This project will advance our long-term goal to integrate post-translational regulatory pathways and obtain a comprehensive understanding of how daily biological rhythms are regulated by diet, nutrition, and timing of metabolic input. This project will have broad significance as misregulation in S- palmitoylation has been linked to a plethora of human diseases including cancer, metabolic, neurological, and immunological disorders.

项目概要 稳健的日常生物节律是动物健康寿命的关键标志，并且对 受生物钟调节。这些细胞自主分子计时器使动物能够适应 环境中可预测的日常变化。时钟控制输出无所不包 生物钟紊乱与多种病理和慢性疾病有关。在 自然世界、环境信号，例如光和温度，启用动物生物钟 来控制进食的时间。因此，营养流入可以提供代谢信号来强化 环境信号，促进细胞生理学的同步性，以平衡新陈代谢和 能源使用。努力了解生物钟的基础及其对生物钟的控制 日常生物节律长期以来一直关注转录水平的调节，作为核心 振荡蛋白是协作控制基因节律表达的转录因子 参与多种细胞过程。最近的研究发现互补的非 转录机制，包括蛋白质翻译后修饰 (PTM) 对于稳健的日常节奏至关重要。该项目的总体目标是增进我们的理解 营养依赖性 PTM 在介导一天中特定时间的代谢调节中的作用 蛋白质的作用是协调日常的生物节律。我们将使用昼夜果蝇模型 测试中心假设，即来自时钟控制的进食活动的代谢信号和 细胞代谢调节细胞蛋白质的节律性 S-棕榈酰化和 S-棕榈酰化 对于维持稳健的日常生物节律是必要的。 S-棕榈酰化是唯一的 可逆脂质 PTM；它是棕榈酸（一种饱和脂肪酸）与半胱氨酸的结合。 S- 棕榈酰化针对从转录因子到膜受体的多种蛋白质， 已知会改变它们的稳定性、活性、定位和蛋白质-蛋白质相互作用。这 该项目的具体目标是研究时钟依赖的机制 代谢信号调节 S-棕榈酰化节律以及这些节律如何受到影响 营养压力（目标 1）；识别在 S-棕榈酰化中表现出每日节律的蛋白质（目标 2）； 并确定棕榈酰化是否调节日常生物节律（目标 3）。该项目将 推进我们的长期目标，整合翻译后监管途径并获得 全面了解饮食、营养和饮食如何调节日常生物节律 代谢输入的时间。该项目将具有广泛的意义，因为 S- 棕榈酰化与多种人类疾病有关，包括癌症、代谢、 神经系统和免疫系统疾病。