Mitochondrial energy metabolism, redox state and sleep

线粒体能量代谢、氧化还原状态和睡眠

• 批准号: MR/X019179/1
• 负责人: Zelie Britton
• 金额: $ 24.02万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Fellowship
• 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=MR%2FX019179%2F1
• 关键词: Mitochondrial; energy; metabolism; redox; state

Sleep disorders are increasingly prevalent, with up to two thirds of adults experiencing disrupted sleep. Sleep disturbance accompanies normal aging and is also a feature of multiple diseases including metabolic disorders, Alzheimer's, Parkinson's, depression and anxiety. Poor sleep can have numerous negative impacts on health, including increased daytime sleepiness, impaired cognitive function and a higher risk of diabetes, obesity and road traffic accidents. There are proven benefits to treating sleep disorders but current medications are limited by side effects of over-sedation, forgetfulness and addiction. This project sets out to better understand how sleep is controlled in a mammalian model. By identifying the processes that control homeostatic sleep drive, we hope to identify novel targets for the development of improved medications for sleep disorders and that such treatments will reduce the risks associated with sleep deprivation. Background It is generally held that there are two main neural systems controlling sleep: the circadian clock aligns the body's internal daily rhythms to those of the sun, enabling, amongst other things, sleep to occur during hours of darkness; and, a homeostatic process that ensures a sufficient quantity of sleep occurs. The homeostatic process should measure the amount of sleep deprivation experienced and, once a sufficient threshold is reached, permit a switch from a wake-state to a sleep-state. Sleep should then reset the switch. In mammals, the sleep-dependent variables and sensor that form this homeostat not fully described. Previous work has identified the hypothalamus, part of the brainstem, as being important for controlling sleep in humans and loss of neurons in this area in aging and in Alzheimer's disease is associated with reduced and fragmented sleep. Research in a flies has identified a group of neurons in an area similar to the mammalian hypothalamus which, when activated, result in sleep. Moreover, sleep deprivation increases the concentration of oxidants in these cells, and the increased levels of oxidants increase the activity of the neurons, providing a clue as to the homeostat mechanism in flies. Therefore, this project will focus on how the ratio of intracellular oxidants and anti-oxidants govern the activity of neurons in the hypothalamus of mice and investigate whether this system thereby controls sleep itself.

睡眠障碍越来越普遍，多达三分之二的成年人都经历过睡眠障碍。睡眠障碍伴随着正常衰老，也是多种疾病的一个特征，包括代谢紊乱、阿尔茨海默氏症、帕金森氏症、抑郁症和焦虑症。睡眠不佳会对健康产生许多负面影响，包括白天嗜睡增加、认知功能受损以及患糖尿病、肥胖和道路交通事故的风险增加。治疗睡眠障碍已被证明有好处，但目前的药物受到过度镇静、健忘和成瘾等副作用的限制。 该项目旨在更好地了解哺乳动物模型中如何控制睡眠。通过确定控制稳态睡眠驱动的过程，我们希望确定开发改进的睡眠障碍药物的新目标，并且此类治疗将降低与睡眠剥夺相关的风险。背景 人们普遍认为，有两个主要的神经系统控制睡眠：生物钟使身体内部的日常节律与太阳的节律保持一致，从而使睡眠能够在黑暗的时间发生；并且，发生确保充足睡眠的稳态过程。稳态过程应该测量所经历的睡眠剥夺的量，并且一旦达到足够的阈值，就允许从清醒状态切换到睡眠状态。然后睡眠应该重置开关。在哺乳动物中，形成这种稳态的依赖于睡眠的变量和传感器尚未得到充分描述。先前的研究已经确定下丘脑（脑干的一部分）对于控制人类睡眠很重要，并且在衰老和阿尔茨海默病中该区域神经元的丧失与睡眠减少和碎片化有关。对果蝇的研究发现，在类似于哺乳动物下丘脑的区域中存在一组神经元，这些神经元被激活后会导致睡眠。此外，睡眠剥夺会增加这些细胞中氧化剂的浓度，而氧化剂水平的增加会增加神经元的活性，这为果蝇的稳态机制提供了线索。 因此，本项目将重点研究细胞内氧化剂和抗氧化剂的比例如何控制小鼠下丘脑神经元的活动，并研究该系统是否从而控制睡眠本身。