Mechanisms of Arousal in Sleep Apnea

描述(由申请人提供)： 该计划项目赠款的目的是确定在阻塞性睡眠呼吸暂停(OSA)期间调节脑电唤醒和呼吸道开放的大脑回路，并基于这些信息设计和测试OSA患者的新疗法。阻塞性睡眠呼吸暂停综合征患者在睡眠时，其呼吸道扩张器肌肉失去张力，导致呼吸道塌陷和呼吸暂停。随着二氧化碳水平的上升，呼吸的尝试逐渐增加，直到最终脑电波唤醒，呼吸道打开，呼吸重新建立。这些觉醒每晚发生多达数百次，使睡眠变得支离破碎，导致认知障碍；加速动脉粥样硬化，增加中风和心肌梗死的风险；以及肥胖引起的代谢综合征，这反过来会使OSA变得更糟，并进一步增加心血管风险。我们的研究人员发现，在某些呼吸暂停周期中，患者可能会产生足够的气道扩张器张力来重新打开气道，而不会引起脑电唤醒。在这类受试者中，延迟脑电唤醒可能允许患者产生足够的呼吸道扩张器音调来避免唤醒。我们的目标是找到药物手段来延迟EEG的唤醒，同时增加呼吸道扩张器的张力，这样OSA患者的呼吸暂停较少，或者如果发生呼吸暂停，能够在没有EEG唤醒的情况下重新建立气道。项目1-3通过识别引起动脉二氧化碳升高的大脑回路来实现第一个目标。这些项目寻求确定二氧化碳唤醒过程中涉及的神经递质和受体，作为药物操作的目标。项目4的重点是控制颧舌肌，这是最大的呼吸道扩张器。它将检查在睡眠期间抑制音调的膝舌肌运动神经元的输入，以便我们可以从药物上增强膝舌肌运动神经元的音调。项目5是一项人体研究，使用我们关于脑电唤醒和颧舌肌控制的假设来产生和测试一种治疗阻塞性睡眠呼吸暂停的新方法。我们希望，随着我们在项目1-4中了解到更多关于大脑回路的知识，我们将在项目中改进我们的治疗方法 5.核心A组织的频繁会议，包括每三周举行一次的调查员会议，也促进了这些项目之间的互动，所有调查员都参加了会议，在这些会议上，项目 轮流介绍他们的进展情况，并接受同事的反馈，以进一步改进他们的工作；以及我们的内部或外部咨询委员会的年度会议，这些委员会提供该领域杰出科学家的意见，为我们的科学方法提供信息和改进。此外，项目1-4共享许多先进的光遗传学和膜片钳生理学方法，这些方法受益于与分子生物学核心B和电生理学核心C的相互作用。长期目标是找到一种药物方法，通过这种方法，至少一部分OSA人群可以减少呼吸暂停和随后的EEG觉醒的频率，从而减少OSA的认知、代谢和心血管后果。

DESCRIPTION (Provided by applicant): The purpose of this Program Project Grant is to identify brain circuitry that regulates EEG arousal and airway opening during obstructive sleep apnea (OSA), and to design and test new therapies in OSA patients based on that information. Patients with OSA lose tone in their airway dilator muscles as they sleep, resulting in collapse of the airway and apnea. As CO2 levels rise, there are progressively more vigorous attempts to breathe, until finally there is EEG arousal, the airway opens, and breathing is re-established. These arousals occur as many as several hundred times per night, fragmenting sleep and resulting in cognitive impairments; accelerated atherosclerosis, and increased risk of stroke and myocardial infarction; and metabolic syndrome with obesity, which in turn makes the OSA worse and further increases cardiovascular risk. Our investigators have found that in some apnea cycles, patients may generate sufficient airway dilator tone to reopen the airway, without EEG arousal. In such subjects, delaying the EEG arousal may permit the patients to generate enough airway dilator tone to avoid arousals. Our goals then are to find pharmacological means to delay EEG arousal while augmenting airway dilator tone, so that OSA patients have fewer apneas, or if they occur, are able to re-establish the airway without EEG arousal. Projects 1-3 work on the first goal by identifying the brain circuitry that causes the arousal to rising arterial CO2. These projects seek to identify the neurotransmitters and receptors involved in CO2 arousal, as targets for pharmacological manipulation. Project 4 focuses on the control of the genioglossus muscle, the largest airway dilator. It will examine the inputs to the genioglossus motor neurons that suppress tone during sleep, so that we can pharmacologically augment genioglossus motor tone. Project 5 is a human study that uses our hypotheses about control of EEG arousal and the genioglossus muscle to generate and test a novel therapeutic approach to OSA. We hope that as we learn more about this brain circuitry in Projects 1-4, we will to refine our treatment methods in Project 5. Interactions among these Projects are also fostered by frequent meetings organized by Core A, including tri-weekly Investigator Meetings, attended by all Investigators, in which the Projects take turns presenting their progress and receiving feedback from colleagues to further improve their work; and by annual meetings of our Internal or External Advisory Boards, which provide input from outstanding scientists in this field that inform and refine our scientific approach. In addition, Projects 1-4 share many cutting edge optogenetic and patch clamp physiology methods that benefit from interactions with the Molecular Biology Core B and Electrophysiology Core C. The long term goal is to find a pharmacological approach through which at least a segment of the OSA population can reduce the frequency of apneas and subsequent EEG arousals, thus reducing the cognitive, metabolic, and cardiovascular consequences of OSA.