Neuropeptidomics of Clock-to-Clock Coupling

时钟与时钟耦合的神经肽组学

基本信息

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
项目类别：
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

项目摘要

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）：生物学中的一个未解决的问题是，是什么协调生物体的昼夜节律？大脑中央昼夜节律之间的协调丧失，其他细胞和组织中的昼夜节律时钟与导致睡眠障碍的系统病理有关。该发现建议的目的是识别将SCN和[胶质]昼夜节律时钟结合起来的肽。对分离培养的周围组织的研究表明，在SCN的缺失下，细胞节奏继续持续，但是相位和周期特性在各种组织中的变化，包括大脑，肝，肺，肺，肌肉，肌肉，肾脏，肾脏，尾巴[和脾[和脾[]。通过脱钩，各种组织函数会失去时间连贯性，并适当地对齐睡眠和清醒周期。关于有机体的昼夜节律钟表的伴侣知之甚少，除了可以扩散的因素足以夹住许多因素。发现从SCN到其他昼夜节律时钟（在大脑和身体）中传达时间的耦合因素已被证明很困难。我们提出了一项研究，该研究采用高级分析肽组技术在千分尺尺度上，并确定肽恢复时钟到锁定协调能力的功能确定，这是一种创新的方法。我们的目的是：1）定义和表征[神经胶质节律的SCN驱动的同步，2）通过肽分析确定已释放的候选偶联肽，3）确定从SCN中释放的候选肽的必要性/足够性/足够的肽偶联肽，以诱导同步的Rhyths of [Glia] cands cand cand cand cand和4）和4）。这些目标的成功完成将使我们有望在动物模型中测试耦合。内部时钟之间失去同步是针对健康和寿命的适应不良的。目前没有方法可以更好地同步或增强内部时钟的耦合。确定有效伴侣节奏的信号在治疗代谢综合征，肥胖，心血管压力和生理下降时具有重大价值，随着衰老的衰老，这一切都表现为每年影响超过1000万美国人的无序睡眠模式。但是，为了实现治疗潜力，必须识别并将其与其他昼夜节律接合的信号识别并放置在时间上。公共卫生相关性：该提案旨在确定在整个睡眠效果周期中提供昼夜节律在身体功能中整合的神经肽。大脑中央昼夜节律之间的协调丧失，其他细胞和组织中的昼夜节律钟表与导致睡眠障碍的系统病理学有关，并且对健康和寿命不良。确定在整个身体中有效伴随昼夜节律的信号将在代谢综合征，肥胖，心血管压力和随着衰老的生理下降方面具有重大价值，所有这些都表现为每年影响超过1000万美国人的睡眠模式；但是，为了实现治疗潜力，必须识别SCN参与其他昼夜节律时钟的信号，并将其放置在时间环境中。