15 BEDREST Effects of bed rest on the circadian organisation of the human transcriptome as a model for temporal dysregulation in an ageing population

15 BEDREST 卧床休息对人类转录组昼夜节律组织的影响作为老龄化人群时间失调的模型

基本信息

  • 批准号:
    BB/N004981/1
  • 负责人:
  • 金额:
    $ 57.83万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2015
  • 资助国家:
    英国
  • 起止时间:
    2015 至 无数据
  • 项目状态:
    已结题

项目摘要

Circadian (about a day) rhythms in behaviour and physiology synchronise our activity to the outside world. The importance of robust, well-synchronised circadian rhythms is evident from the negative effects experienced during jet lag or sleep deprivation, and also disruption of sleep and circadian rhythms that occurs during spaceflight. The strength and the timing of circadian signals become reduced and disrupted during spaceflight and ageing and may account for many changes observed with sleep/wake activity in astronauts and the elderly. Circadian clocks around the body regulate most physiological processes such as metabolism, cardiovascular function, and the immune system and both long duration spaceflight and ageing may disrupt the circadian regulation of these processes and be associated with related negative health outcomes.Circadian clocks also regulate hormones such as melatonin (which peaks in the night) and cortisol (which peaks on awakening). Cortisol is an important circulating signal that regulates the expression of many genes, including those that make proteins involved in immunity and inflammation. Cortisol secretion is also disrupted during spaceflight and ageing and could change the regulation of the expression of many genes.Blood circulates around the body and is increasingly viewed as a 'window' on the whole-body state. For example, blood biomarkers are now used to diagnose and to monitor disease progression in many different diseases ranging from Alzheimer's to cancer. Temporal organisation in the expression of genes to make proteins is important - certain proteins need to be made at particular times of day or night - and in any given tissue around 6-10% of all genes are expressed with a circadian rhythm, including in blood. In two separate human studies, we have shown that one-week of insufficient sleep or mistimed sleep (as occurs in jet lag) leads to dramatic disruption (both timing and amplitude) to the circadian rhythms of blood gene expression. This included disruption to genes normally expressed during the day (immune response, inflammation, oxidative stress) and those normally expressed during the night (regulation of protein synthesis), as well as core clock genes central to the generation of circadian rhythmicity itself.Spaceflight and its bed rest model result in circadian disruption to melatonin and cortisol. This circadian disruption likely extends to the temporal disruption of gene expression in blood, although nobody has investigated this to date. Thus, during bed rest there is disruption to circadian signals, elevated circulating cortisol, changes in blood circulation, changes to cardiovascular function, including suppressed immune function, all of which are also found in ageing. Therefore, many of the negative health effects found in astronauts and the elderly could be directly associated with temporal disruption to the circadian regulation of gene expression in blood. The main aim of the research proposed here is to perform a careful study of gene expression in blood of people who are undertaking a bed rest protocol. By comparing a series of blood samples collected through the day and night at different stages during the bed rest period with similar timed samples collected at baseline and during recovery, we will be able to identify networks of genes whose disruption affects specific biological processes, which may include the immune system and other processes not yet shown to be affected by bed rest. It is difficult to study these effects directly during long duration spaceflight or during ageing over extended time periods and the bed rest protocol provides a practical means to explore changes in defined laboratory conditions. It is assumed that bed rest models ageing and we will also use this model to assess the methodological aspects of whether blood sampling is a viable approach to monitor effects of temporal disruption in ageing and to assess the effects of countermeasures.
行为和生理上的昼夜节律(大约一天)使我们的活动与外部世界同步。从时差或睡眠剥夺期间所经历的负面影响以及太空飞行期间发生的睡眠和昼夜节律中断中可以明显看出稳健,良好同步的昼夜节律的重要性。昼夜节律信号的强度和时间在航天飞行和衰老过程中会减少和中断,这可能是宇航员和老年人睡眠/清醒活动中观察到的许多变化的原因。人体的生物钟调节着大多数生理过程,如新陈代谢、心血管功能和免疫系统,长时间的太空飞行和衰老可能会破坏这些过程的生物钟调节,并与相关的负面健康结果有关。生物钟还调节激素,如褪黑激素(在夜间达到峰值)和皮质醇(在醒来时达到峰值)。皮质醇是一种重要的循环信号,调节许多基因的表达,包括那些制造参与免疫和炎症的蛋白质的基因。皮质醇的分泌在航天飞行和衰老过程中也会受到干扰,并可能改变许多基因表达的调节。血液在体内循环,越来越多地被视为全身状态的“窗口”。例如,血液生物标志物现在用于诊断和监测从阿尔茨海默氏症到癌症的许多不同疾病的疾病进展。基因表达的时间组织是重要的-某些蛋白质需要在白天或晚上的特定时间产生-在任何给定的组织中,大约6-10%的基因都以昼夜节律表达,包括血液。在两项独立的人体研究中,我们已经证明,一周的睡眠不足或睡眠时间不正确(如时差)会导致血液基因表达的昼夜节律发生戏剧性的破坏(时间和幅度)。这包括对白天正常表达的基因(免疫反应、炎症、氧化应激)和晚上正常表达的基因(蛋白质合成的调节)的破坏,以及对昼夜节律本身产生至关重要的核心时钟基因的破坏。这种昼夜节律的破坏可能会延伸到血液中基因表达的时间破坏,尽管迄今为止还没有人对此进行过研究。因此,在卧床休息期间,昼夜节律信号被破坏,循环皮质醇升高,血液循环变化,心血管功能变化,包括免疫功能抑制,所有这些都在衰老中发现。因此,在宇航员和老年人中发现的许多负面健康影响可能与血液中基因表达的昼夜节律调节的时间中断直接相关。本文提出的研究的主要目的是对正在进行卧床休息协议的人的血液中的基因表达进行仔细研究。通过比较在卧床休息期间不同阶段白天和夜晚收集的一系列血液样本与在基线和恢复期间收集的类似定时样本,我们将能够识别基因网络,这些基因网络的破坏会影响特定的生物过程,其中可能包括免疫系统和其他尚未显示受卧床休息影响的过程。在长时间航天飞行期间或在长时间老化期间,很难直接研究这些影响,而卧床休息方案为探索确定的实验室条件下的变化提供了一种切实可行的手段。假设卧床休息模型老化,我们也将使用这个模型来评估方法学方面的血液采样是否是一个可行的方法来监测老化的时间中断的影响,并评估对策的影响。

项目成果

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Simon Archer其他文献

Profit-sharing investment accounts in Islamic banks: Regulatory problems and possible solutions
  • DOI:
    10.1057/jbr.2009.9
  • 发表时间:
    2009-09-09
  • 期刊:
  • 影响因子:
    1.500
  • 作者:
    Simon Archer;Rifaat Ahmed Abdel Karim
  • 通讯作者:
    Rifaat Ahmed Abdel Karim
Visual pigments in the individual rods of deep-sea fishes
深海鱼类个体视杆中的视觉色素
259 EXPRESSION OF CIRCADIAN CLOCK GENE PERIOD 2 IN THE MAMMALIAN BLADDER IDENTIFIED BY REAL-TIME IMAGING WITH LUCIFERASE REPORTER GENE
  • DOI:
    10.1016/j.juro.2012.02.316
  • 发表时间:
    2012-04-01
  • 期刊:
  • 影响因子:
  • 作者:
    Changhao Wu;Guiping Sui;Simon Archer;Ying Chen
  • 通讯作者:
    Ying Chen
L'anguille en voit de toutes les couleurs
  • DOI:
    10.1016/s0294-3506(98)80010-0
  • 发表时间:
    1998-06-01
  • 期刊:
  • 影响因子:
  • 作者:
    Simon Archer
  • 通讯作者:
    Simon Archer
Financial Contracting, Governance Structures and the Accounting Regulation of Islamic Banks: An Analysis in Terms of Agency Theory and Transaction Cost Economics
  • DOI:
    10.1023/a:1009985419353
  • 发表时间:
    1998-06-01
  • 期刊:
  • 影响因子:
    4.000
  • 作者:
    Simon Archer;Rifaat Ahmed Abdel Karim;Talla Al-Deehani
  • 通讯作者:
    Talla Al-Deehani

Simon Archer的其他文献

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{{ truncateString('Simon Archer', 18)}}的其他基金

Genetic and phenotypic outputs of the circadian clock in Per3 knock-out mice and humanised Per3 knock-in mice
Per3 敲除小鼠和人源化 Per3 敲入小鼠生物钟的遗传和表型输出
  • 批准号:
    BB/E003672/1
  • 财政年份:
    2007
  • 资助金额:
    $ 57.83万
  • 项目类别:
    Research Grant

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联合缺氧卧床21天对脑血流调节的影响
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    2012
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