Neuropeptidomics of Clock-to-Clock Coupling

时钟与时钟耦合的神经肽组学

• 批准号: 7924746
• 负责人: Martha U Gillette
• 金额: $ 47.55万
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7924746
• 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(申请人提供)：生物学中一个中心悬而未决的问题是，生物体的生物钟是什么协调的？大脑的中央生物钟、视交叉上核(SCN)和其他细胞和组织的生物钟之间的协调缺失与导致睡眠障碍的系统病理有关。这项发现计划的目标是识别连接SCN和[神经胶质]生物钟的多肽。对分离培养的外周组织的研究表明，在没有SCN的情况下，细胞节律持续，但不同组织的相态和周期特性发生变化，包括脑、肝、肺、肌肉、肾脏、尾巴[和脾]。随着分离，各种组织功能失去了时间上的一致性，并与睡眠和清醒的日常周期保持适当的一致性。人们对生物体生物钟的关联知之甚少，除了扩散因素足以吸引许多生物体的生物钟。事实证明，发现从SCN到[大脑和身体]其他生物钟传递一天中的时间的耦合因素是困难的。我们提出了一项研究，将先进的分析多肽技术应用于微米级，并结合多肽恢复时钟对时钟协调的能力的功能确定，这是一种创新的方法。我们的目标是：1)定义和表征SCN驱动的[Glia]节律同步的诱导；2)通过多肽分析识别释放的候选偶联多肽；3)确定SCN释放的候选偶联多肽对诱导[Glia]时钟同步节律的必要性/充分性；4)表征和评估候选偶联多肽。这些目标的成功完成将为我们在动物模型中测试耦合做好准备。内部生物钟之间失去同步对健康和长寿是不适应的。目前还没有更好地同步或增强内部时钟的耦合的方法。识别有效结合昼夜节律的信号将在治疗代谢综合征、肥胖症、心血管压力和随年龄增长而出现的生理衰退方面具有重要价值，所有这些都表现为睡眠模式紊乱，每年影响1000多万美国人。然而，为了实现治疗潜力，SCN与其他昼夜节律时钟的信号必须被识别并放置在时间背景下。公共卫生相关性：这项提案试图确定在整个睡眠-清醒周期中提供昼夜节律与身体功能整合的神经肽。大脑中的中央生物钟、视交叉上核(SCN)和其他细胞和组织中的生物钟之间的协调缺失与导致睡眠障碍的系统病理有关，并不适应健康和长寿。识别有效结合全身昼夜节律的信号将在治疗代谢综合征、肥胖、心血管应激和随年龄增长而出现的生理衰退方面具有重要价值，所有这些都表现为每年影响1000多万美国人的紊乱睡眠模式；然而，为了实现治疗潜力，必须识别SCN与其他昼夜节律相结合的信号，并将其置于时间背景中。