Neuropeptidomics of Clock-to-Clock Coupling

时钟与时钟耦合的神经肽组学

• 批准号: 7736240
• 负责人: Martha U Gillette
• 金额: $ 49.19万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7736240
• 关键词: Affect; Affinity; Aging; American; Animal Model; Argipressin; Astrocytes; Behavior; Biological Clocks; Biology; Blocking Antibodies; Brain; Brain region; Cardiovascular system; Cell Line; Cells; Chimeric Proteins; Circadian Rhythms; Clock protein; Coculture Techniques; Collaborations; Coupled; Couples; Coupling; Dependence; Electrospray Ionization; Gene Expression; Genes; Glial Fibrillary Acidic Protein; Glutamates; Goals; Hamsters; Health; Incubated; Kidney; Knock-out; Lasers; Lead; Lesion; Liquid Chromatography; Liver; Longevity; Luciferases; Lung; Mass Spectrum Analysis; Mediating; Metabolic syndrome; Methods; Microtubule-Associated Protein 2; Modeling; Molecular; Monitor; Mouse Cell Line; Mus; Muscle; Nature; Neurobiology; Neuroglia; Neurons; Neuropeptides; Obesity; Optic Nerve; Organism; Output; Pathology; Pattern; Peptide Signal Sequences; Peptides; Peripheral; Phase; Physiological; Play; Post-Translational Protein Processing; Procedures; Process; Production; Property; Proteins; Proteomics; Protocols documentation; Reagent; Regulation; Reporter; Role; Running; Sampling; Science; Screening procedure; Signal Transduction; Sleep; Sleep Disorders; Sleep Wake Cycle; Slice; Solid; Solutions; Son; Spleen; Stress; Synapses; System; Tail; Techniques; Technology; Testing; Therapeutic; Time; Tissues; Transgenes; Transgenic Mice; Vasoactive Intestinal Peptide; Wakefulness; base; circadian pacemaker; experience; immunocytochemistry; innovation; knock-down; luciferin; luminescence; mutant; novel; postnatal; promoter; public health relevance; receptor; release factor; research study; secretion process; suprachiasmatic nucleus; supraoptic nucleus; tissue culture; tissue/cell culture; tool

Description (provided by applicant): A central unsolved question in biology is, What coordinates an organism's circadian clocks? Loss of coordination between the central circadian clock in the brain, the suprachiasmatic nucleus (SCN), and circadian clocks in other cells and tissues has been implicated in systems pathologies that lead to sleep disorders. The goal of this discovery proposal is to identify peptides that couple the SCN and [glial] circadian clocks. Studies of peripheral tissues cultured in isolation have revealed that in the SCN's absence, cellular rhythms continue but phase and period properties change in diverse tissues, including brain, liver, lung, muscle, kidney, tail [and spleen]. With decoupling, the various tissue functions lose temporal coherence as well as appropriate alignment to the daily cycle of sleep and wakefulness. Little is known about what couples an organism's circadian clocks, except that diffusible factors are sufficient to entrain many. Discovering coupling factors that communicate time-of-day from SCN to other circadian clocks [in brain and body] has proven difficult. We propose a study applying advanced analytical peptidomic techniques on a micrometer scale coupled with functional determinations of the ability of peptides to restore clock-to-clock coordination, an innovative approach. We aim to: 1) define and characterize induction of SCN-driven synchronization of [glia] rhythms, 2) identify released candidate coupling peptides by peptidomic analysis, 3) determine the necessity/sufficiency of candidate coupling peptides released from the SCN for inducing synchronous rhythms of [glia] clocks, and 4) characterize and evaluate candidate coupling peptides. Successful completion of these aims will poise us for testing coupling in animal models. Loss of synchrony among internal clocks is maladaptive for health and longevity. There are no current approaches to better synchronize or enhance coupling of the internal clocks. Identifying signals that effectively couple circadian rhythms will have major value in treatment of metabolic syndrome, obesity, cardiovascular stress, and physiological decline with aging, all of which manifest with disordered sleep patterns that affect more than 10 million Americans each year. However, to realize therapeutic potential, signals by which the SCN engages other circadian clocks must be identified and placed in temporal context. PUBLIC HEALTH RELEVANCE: This proposal seeks to identify neuropeptides that provide integration of circadian rhythms in body function across the sleep-wake cycle. Loss of coordination between the central circadian clock in the brain, the suprachiasmatic nucleus (SCN), and circadian clocks in other cells and tissues has been implicated in systems pathologies that lead to sleep disorders, and is maladaptive for health and longevity. Identifying signals that effectively couple circadian rhythms throughout the body will have major value in treatment of metabolic syndrome, obesity, cardiovascular stress, and physiological decline with aging, all of which manifest with disordered sleep patterns that affect more than 10 million Americans each year; however, to realize therapeutic potential, signals by which the SCN engages other circadian clocks must be identified and placed in a temporal context.

描述（由申请人提供）：生物学中一个未解决的核心问题是，什么协调生物体的生物钟？大脑中枢生物钟、视交叉上核 (SCN) 和其他细胞和组织中生物钟之间的协调丧失与导致睡眠障碍的系统病理有关。这一发现提案的目标是鉴定连接 SCN 和[神经胶质]生物钟的肽。对隔离培养的外周组织的研究表明，在视交叉上核缺失的情况下，细胞节律仍然存在，但不同组织（包括脑、肝、肺、肌肉、肾、尾[和脾]）的相位和周期特性发生变化。随着解耦，各种组织功能失去时间一致性以及与每日睡眠和觉醒周期的适当对齐。人们对生物体生物钟的耦合因素知之甚少，只知道扩散因素足以吸引许多因素。事实证明，发现将时间从 SCN 传递到其他生物钟（大脑和身体）的耦合因素非常困难。我们提出了一项研究，应用先进的微米级分析肽组学技术，并结合肽恢复时钟到时钟协调能力的功能测定，这是一种创新方法。我们的目标是：1）定义和表征SCN驱动的神经胶质细胞节律同步的诱导，2）通过肽组学分析识别释放的候选偶联肽，3）确定从SCN释放的候选偶联肽用于诱导神经胶质细胞时钟同步节律的必要性/充分性，4）表征和评估候选偶联肽。成功完成这些目标将为我们在动物模型中测试耦合做好准备。内部时钟之间失去同步不利于健康和长寿。当前没有方法可以更好地同步或增强内部时钟的耦合。识别有效耦合昼夜节律的信号对于治疗代谢综合征、肥胖、心血管压力和随年龄增长而出现的生理衰退具有重要价值，所有这些都表现为睡眠模式紊乱，每年影响超过 1000 万美国人。然而，为了实现治疗潜力，必须识别 SCN 与其他生物钟相结合的信号并将其置于时间背景中。公共健康相关性：该提案旨在识别在整个睡眠-觉醒周期中将昼夜节律整合到身体功能中的神经肽。大脑中央生物钟、视交叉上核 (SCN) 和其他细胞和组织中生物钟之间的协调丧失与导致睡眠障碍的系统病理有关，并且不利于健康和长寿。识别有效耦合全身昼夜节律的信号对于治疗代谢综合征、肥胖、心血管压力和随年龄增长而出现的生理衰退具有重要价值，所有这些都表现为睡眠模式紊乱，每年影响超过 1000 万美国人；然而，为了实现治疗潜力，必须识别 SCN 与其他生物钟相结合的信号并将其置于时间背景中。