The role of Salt Inducible Kinases in regulating sleep

盐诱导激酶在调节睡眠中的作用

• 批准号: BB/W016486/1
• 负责人: Aarti Jagannath
• 金额: $ 77.49万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW016486%2F1
• 关键词: role; Salt; Inducible; Kinases; regulating

Despite the growing appreciation of the fundamental importance of sleep and circadian rhythms across multiple domains of health, our understanding of why we sleep and the molecular mechanisms that underpin this critical behaviour, remain largely unknown. We propose to study the fundamental biology of how sleep is signalled at a molecular, neuronal and behavioural level, to identify the molecular pathways that regulate sleep. In order for sleep to have its restorative effects, synapses - the points at which nerve impulses pass information from one neuron to another - must be remodelled during sleep to encode fresh memories and experiences. Recent transformative research shows that proteins at the synapse are tagged by phosphorylation in a manner that tracks the time spent awake, and that this may underlie the basis of how synapses can be remodelled during sleep. Proteins are phosphorylated by kinases, and we have shown previously that Salt Inducible Kinase 1 regulates circadian rhythms in the brain. Building upon this work, we propose experiments that will investigate the role of the Salt Inducible Kinase (SIK) family on the regulation of synaptic proteins and their role in the regulation of sleep. Our approaches will include monitoring sleep and circadian rhythms in genetically altered mice that express inactive versions of the individual SIKs. The mice will be exposed to challenges that alter sleep and circadian rhythms in different ways. These include sleep deprivation, wake or sleep promoting drugs such as caffeine, or nocturnal light exposure. We will then assess the mice for their resulting sleep and circadian behaviour and protein phosphorylation at the synapse. We will also examine whether the changes in protein phosphorylation affect how information is transmitted at the synapse by recording electrical activity. We predict that the loss of activity of SIKs will impair or enhance certain aspects of protein phosphorylation that are essential for the induction of sleep. Collectively, these experiments will provide an understanding of the key pathways by which sleep is regulated at the molecular level.

尽管人们越来越认识到睡眠和昼夜节律在多个健康领域的重要性，但我们对睡眠的理解以及支撑这种关键行为的分子机制在很大程度上仍然是未知的。我们建议研究睡眠如何在分子，神经元和行为水平上发出信号的基础生物学，以确定调节睡眠的分子途径。为了使睡眠具有恢复作用，突触--神经冲动将信息从一个神经元传递到另一个神经元的点--必须在睡眠期间重塑，以编码新鲜的记忆和经历。最近的变革性研究表明，突触处的蛋白质通过磷酸化以跟踪清醒时间的方式标记，这可能是突触在睡眠期间如何重塑的基础。蛋白质被激酶磷酸化，我们之前已经证明盐诱导激酶1调节大脑的昼夜节律。在这项工作的基础上，我们提出的实验，将调查的作用，盐诱导激酶（SIK）家族的突触蛋白的调节和它们的作用，在调节睡眠。我们的方法将包括监测睡眠和昼夜节律的基因改变小鼠表达个别SIKs的非活性版本。小鼠将暴露于以不同方式改变睡眠和昼夜节律的挑战。这些包括睡眠剥夺，唤醒或睡眠促进药物，如咖啡因，或夜间光照。然后，我们将评估小鼠的睡眠和昼夜节律行为以及突触处的蛋白质磷酸化。我们还将通过记录电活动来研究蛋白质磷酸化的变化是否影响信息在突触处的传递。我们预测SIKs活性的丧失将损害或增强蛋白磷酸化的某些方面，这些方面对于诱导睡眠至关重要。总的来说，这些实验将提供对睡眠在分子水平上调节的关键途径的理解。

项目成果

The multiple roles of salt-inducible kinases in regulating physiology.

盐诱导激酶在调节生理学中的多重作用。

• DOI: 10.1152/physrev.00023.2022
• 发表时间: 2023-07-01
• 期刊: PHYSIOLOGICAL REVIEWS
• 影响因子: 33.6
• 作者: Jagannath, Aarti;Taylor, Lewis;Ru, Yining;Wakaf, Zeinab;Akpobaro, Kayomavua;Vasudevan, Sridhar;Foster, Russell G.
• 通讯作者: Foster, Russell G.