Redox Control of Sleep

睡眠障碍是最常见的医疗问题之一，估计在一般人群中患病率为10-15%，在老年人中患病率为30-60%。它们伴随着许多医学、精神和神经疾病。疲劳和失眠是内分泌和代谢紊乱的常见症状，而睡眠不足是生活方式选择、工作或个人压力、慢性疼痛或呼吸功能障碍的结果，是糖尿病和肥胖的一个确定的危险因素。同样复杂的因果关系也是精神疾病睡眠困难的特征。失眠和嗜睡是重度抑郁症的核心症状，而睡眠需求减少是躁狂发作的典型特征。睡眠不足经常引发发作，导致复发，并增加药物滥用合并症的风险。在许多神经退行性疾病中，包括阿尔茨海默氏症和帕金森氏症，在正常衰老过程中发生的睡眠断裂会加速或加剧。促进睡眠的神经元受到损伤，可能在一定程度上解释了阿尔茨海默病患者睡眠质量差的特点。在帕金森病中，睡眠中断是前驱阶段最具诊断性的生物标志物之一，也是有症状疾病中最常见的非运动体征之一。尽管睡眠障碍很普遍，而且治疗睡眠障碍可以改善许多合并症，但治疗选择仍然有限。其中包括改善睡眠卫生的行为干预，以及使用苯二氮卓类药物和抗组胺类镇静剂。这些药物与广泛的副作用有关，如早晨镇静、反弹性失眠、顺行性遗忘、混乱和损伤以及成瘾。新的治疗概念的发展需要对睡眠的神经元控制有更深入的了解。本项目将测试我们在果蝇身上发现的睡眠调节机制的普遍性，并检查其作为药物干预目标的适用性。该机制的核心是钾通道β亚基，它在稳定结合的烟酰胺（NADPH）辅助因子的帮助下感知细胞氧化还原化学的变化。睡眠不足会增加睡眠诱导神经元中的线粒体活性氧，这是通过将β亚基转化为NADP+结合形式来记录的。辅因子的氧化通过加速膜复极而提高动作电位的频率，从而促进睡眠。能量代谢、氧化应激和睡眠这三个独立影响寿命、衰老和退行性疾病的过程，因此在机制上相互联系。该计划将追求三个目标：项目一将研究钾通道β亚基是否调节哺乳动物的睡眠。我们将量化携带三个KCNAB基因突变的小鼠的睡眠，无论是单独的还是组合的，并通过将野生型β亚基重新引入受限的大脑区域来定位与睡眠相关的作用位点。项目2将测试小分子氧化还原酶底物，如过氧化脂质的分解产物，是否能稳定地改变结合辅因子的氧化还原电位。如果辅因子的NADP+:NADPH比值编码了大脑的睡眠债务或清醒时间记录，那么这些分子就代表了睡眠调节药物的原型。项目3将寻找能够刺激（或阻止）睡眠的化学物质，作为β亚基底物，但具有比过氧化脂质更有利的药理特性。总之，这一规划有望为合理治疗睡眠障碍的新方法奠定基础，可能带来重大的健康和经济效益。

Sleep disturbances are among the most common medical problems, with an estimated prevalence of 10-15% in the general and 30-60% in the older population. They accompany many medical, psychiatric, and neurological conditions.Fatigue and insomnia are common symptoms of endocrine and metabolic disorders, whereas inadequate sleep, be it a consequence of lifestyle choices, work or personal pressures, chronic pain, or respiratory dysfunction, is an established risk factor for diabetes and obesity.Similarly complex cause-and-effect relationships also characterize the sleeping difficulties in psychiatric illnesses. Insomnia and hypersomnia are core symptoms of major depressive disorder, while reduced sleep need is a defining feature of manic episodes. Inadequate sleep often triggers episodes, contributes to relapse, and increases the risk of substance abuse comorbidity.The sleep fragmentation that occurs during normal ageing is accelerated or augmented in many neurodegenerative diseases, including Alzheimer's and Parkinson's. Injury to sleep-promoting neurons may account, in part, for the characteristically poor sleep quality of Alzheimer's patients. In Parkinson's disease, sleep disruptions are among the most diagnostic biomarkers during the prodromal stage and among the most common non-motor signs in symptomatic disease.Despite the prevalance of sleep disturbances and the proven benefit of treating them for improving many comorbid conditions, therapeutic options remain limited. They include behavioural interventions to improve sleep hygiene and the use of benzodiazepine and antihistamine sedatives. These medications are associated with a wide range of adverse effects, such as morning sedation, rebound insomnia, anterograde amnesia, confusion and injury, and addiction.The development of new therapeutic concepts requires a deeper understanding of the neuronal control of sleep. The present programme will test the generality of a sleep-regulatory mechanism we have discovered in Drosophila and examine its suitability as a target for pharmacological intervention. The centrepiece of this mechanism is a potassium channel beta-subunit that senses changes in cellular redox chemistry with the help of a stably bound nicotinamide (NADPH) cofactor. Sleep loss elevates mitochondrial reactive oxygen species in sleep-inducing neurons, which register this rise by converting the beta-subunit to the NADP+-bound form. The oxidation of the cofactor boosts the frequency of action potentials by accelerating membrane repolarization and thereby promotes sleep. Energy metabolism, oxidative stress, and sleep, three processes implicated independently in lifespan, ageing, and degenerative disease, are thus mechanistically connected.The proposed programme will pursue three goals:Project 1 will examine whether potassium channel beta-subunits regulate sleep in mammals. We will quantify sleep in mice carrying mutations in the three KCNAB genes, singly or in combination, and localize the sleep-relevant sites of action by re-introducing wild-type beta-subunits into confined brain regions.Project 2 will test whether small-molecule oxidoreductase substrates, such as breakdown products of peroxidized lipids, can stably alter the redox potential of the bound cofactor. If the NADP+:NADPH ratio of the cofactor encodes the brain's record of sleep debt or waking time, such molecules represent prototypes of sleep-regulatory drugs. Project 3 will search for chemicals that can stimulate (or prevent) sleep by acting as beta-subunit substrates but possess more favourable pharmacological properties than peroxidized lipids. Together, this programme promises to lay the foundation for a rational new approach to the treatment of sleep disorders, with potentially significant health and economic benefits.