Determining the membrane circadian clock across evolution

确定进化过程中的膜生物钟

• 批准号: BB/W000865/1
• 负责人: James Hodge
• 金额: $ 69.54万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW000865%2F1
• 关键词: Determining; membrane; circadian; clock; across

Circadian clocks are found in all animals and are fundamental to life allowing the study of clocks in animals that are easy to keep, age and do experiments with. Hence, nearly all clock genes and how they form a molecular clock were identified in flies and later found to be conserved in mice and humans. This and the fact that circadian rhythms profoundly affect all aspects of physiology and health, led to Nobel prizes being awarded to fly circadian researchers. The molecular clock consists of clock genes that switch themselves on and off every 24hours in the clock neurons of the brain. In our '24/7 society', an increasing proportion of the population experience de-synchronisation of their circadian clock with the external world, due to shift-work, access to technology, anti-sleep drugs, irregular sleep and eating patterns. This so-called 'social jetlag', like jetlag can contribute to an alarming increase in health risks, being associated with the mental health crisis, cancer, diabetes, addiction, metabolic and sleep disorders, with 30% of people experiencing insomnia. Furthermore 40-70% of the elderly population experiences chronic sleep disturbances with Alzheimer's and Parkinson's causing more pronounced circadian and sleep deficits contributing to their pathology. We have also shown that insect clocks are important for pollinator health and food security and are negatively impacted by insecticides that target clock neuron ion channels. The master clock in the brain consists of a neural circuit of clock neurons that receive and transmit time of day information via electrical signals that are bi-directionally influenced by the molecular clock. Electrical signals are generated by ion channels in the membrane which control the release of chemical signals between neurons relaying temporal information throughout the clock and to the rest of the brain and body. We have shown that the membrane of clock neurons is more electrically excitable in the day than at night in flies and mice. These ion channel generated electrical signals are thought to help synchronise clock neurons and interact with the molecular clock to generate an overall strong and sustained circadian rhythm. We have shown this weakens with age. However there is a knowledge gap in the exact components and mechanism of this so-called membrane clock and how it is affected by ageing. We wish to determine the clock neuron ion channels that generate day v night differences in clock neuron excitability in flies, mice and ageing. Therefore our aim is to decipher the components and mechanism of the membrane clock using flies, mouse and computational models testing the hypothesis that there is a conserved set of ion channels that generate daily electrical variations in fly and mouse clock neurons. This will reveal the electrical basis of diurnal v nocturnal behaviour and whether by manipulating the membrane clock to become mouse like you can make a fly become nocturnal. We will test if ageing alters these daily changes and what effect it has on circadian rhythms and health span. Therefore the objectives are:1: In flies and mice determine which ion channels generate the day/night differences in electrical activity of clock neurons2: In flies and mice generate ion channel-based computational models of clock neurons and use dynamic clamp (DC) to test causality3: In flies determine the circadian consequences of making specific changes in clock neuron ion channels predicted by our models and DC4: In flies, determine the effect of ageing on ion channels that generate day/night differences in clock neuron electrical activityThis research will identify the clock neuron ion channels required to generate robust circadian rhythms throughout the health span revealing interventions that we will test to rejuvenate the excitability of old clock neurons and reverse circadian ageing. This will develop new drug targets and treatments for circadian, sleep and ageing disorders.

生物钟存在于所有动物中，是生命的基础，允许研究易于保持，老化和做实验的动物的生物钟。因此，几乎所有的时钟基因以及它们如何形成分子时钟都是在苍蝇中发现的，后来发现在小鼠和人类中也是保守的。这一点以及昼夜节律深刻影响生理和健康的各个方面的事实，导致诺贝尔奖被授予飞行昼夜节律研究人员。分子钟由时钟基因组成，这些基因在大脑的时钟神经元中每24小时打开和关闭一次。在我们的“24/7社会”中，由于轮班工作，获得技术，抗睡眠药物，不规则的睡眠和饮食模式，越来越多的人口经历他们的生物钟与外部世界不同步。这种所谓的“社会时差”，就像时差一样，会导致健康风险惊人地增加，与心理健康危机、癌症、糖尿病、成瘾、代谢和睡眠障碍有关，30%的人患有失眠症。此外，40-70%的老年人患有阿尔茨海默氏症和帕金森氏症的慢性睡眠障碍，导致更明显的昼夜节律和睡眠不足，从而导致其病理学。我们还表明，昆虫钟对传粉者健康和粮食安全很重要，并且受到针对时钟神经元离子通道的杀虫剂的负面影响。大脑中的主时钟由时钟神经元的神经回路组成，这些神经元通过受分子时钟双向影响的电信号接收和传输一天中的时间信息。电信号是由细胞膜中的离子通道产生的，这些离子通道控制神经元之间化学信号的释放，将时间信息传递到整个时钟以及大脑和身体的其他部分。我们已经证明，果蝇和小鼠的生物钟神经元膜在白天比在晚上更容易电兴奋。这些离子通道产生的电信号被认为有助于同步时钟神经元，并与分子时钟相互作用，以产生整体强烈和持续的昼夜节律。我们已经证明了这一点随着年龄的增长而减弱。然而，在这个所谓的膜时钟的确切组成部分和机制以及它如何受到衰老的影响方面存在知识空白。我们希望确定产生昼夜差异的时钟神经元兴奋性在苍蝇，小鼠和老化的时钟神经元离子通道。因此，我们的目标是使用苍蝇，小鼠和计算模型来破译膜时钟的组件和机制，以测试存在一组保守的离子通道的假设，这些离子通道在苍蝇和小鼠时钟神经元中产生每日的电变化。这将揭示昼夜行为的电基础，以及是否通过操纵膜钟变成老鼠一样，你可以让苍蝇变成夜间活动的。我们将测试衰老是否会改变这些日常变化，以及它对昼夜节律和健康寿命的影响。因此，目标是：1：在苍蝇和小鼠中，确定哪些离子通道产生时钟神经元电活动的昼夜差异2：在苍蝇和小鼠中，生成基于离子通道的时钟神经元计算模型，并使用动态钳（DC）来测试电容性3：在苍蝇中，确定我们的模型和DC预测的时钟神经元离子通道发生特定变化的昼夜节律后果4：在苍蝇中，确定老化对产生日/生物钟神经元电活动的夜间差异这项研究将确定生物钟神经元离子通道，这些离子通道在整个健康期间产生强大的昼夜节律，揭示我们将测试的干预措施，以恢复旧生物钟神经元的兴奋性并逆转昼夜节律。老化这将开发针对昼夜节律、睡眠和衰老障碍的新药物靶点和治疗方法。

项目成果

DYRK1a Inhibitor Mediated Rescue of Drosophila Models of Alzheimer's Disease-Down Syndrome Phenotypes.

• DOI: 10.3389/fphar.2022.881385
• 发表时间: 2022
• 期刊: FRONTIERS IN PHARMACOLOGY
• 影响因子: 5.6
• 作者: Zhu, Bangfu;Parsons, Tom;Stensen, Wenche;Mjoen Svendsen, John S.;Fugelli, Anders;Hodge, James J. L.
• 通讯作者: Hodge, James J. L.

Additional file 1 of Increased interaction between endoplasmic reticulum and mitochondria following sleep deprivation

睡眠剥夺后内质网和线粒体之间相互作用增加的附加文件 1

• DOI: 10.6084/m9.figshare.22598968
• 发表时间: 2023
• 作者: Aboufares El Alaoui A

Increased interaction between endoplasmic reticulum and mitochondria following sleep deprivation.

• DOI: 10.1186/s12915-022-01498-7
• 发表时间: 2023-01-04
• 期刊: BMC BIOLOGY
• 影响因子: 5.4
• 作者: El Alaoui, Amina Aboufares;Buhl, Edgar;Galizia, Sabrina;Hodge, James J. L.;de Vivo, Luisa;Bellesi, Michele
• 通讯作者: Bellesi, Michele

Keep It Simple: Using README Files to Advance Standardization in Chronobiology.

• DOI: 10.3390/clockssleep5030033
• 发表时间: 2023-08-30
• 期刊: Clocks & sleep
• 影响因子: 3.1

Additional file 4 of Increased interaction between endoplasmic reticulum and mitochondria following sleep deprivation

睡眠剥夺后内质网和线粒体之间相互作用增加的附加文件 4

• DOI: 10.6084/m9.figshare.22598977
• 发表时间: 2023
• 作者: Aboufares El Alaoui A