Mechanisms of Arousal in Sleep Apnea

描述（由申请人提供）： 这项计划项目资助的目的是确定在阻塞性睡眠呼吸暂停（OSA）期间调节EEG唤醒和气道开放的脑回路，并根据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症患者在睡眠时呼吸道扩张肌张力下降，导致呼吸道塌陷和呼吸暂停。随着CO2水平的升高，呼吸的尝试越来越强烈，直到最后出现EEG唤醒，气道打开，呼吸重新建立。这些觉醒每晚发生多达数百次，使睡眠碎片化并导致认知障碍;加速动脉粥样硬化，并增加中风和心肌梗死的风险;以及代谢综合征伴肥胖，这反过来使OSA恶化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音，以重新打开气道，而无需EEG唤醒。在这样的受试者中，延迟EEG唤醒可以允许患者产生足够的气道扩张器音调以避免唤醒。因此，我们的目标是找到药理学方法来延迟EEG唤醒，同时增强气道扩张器张力，以便OSA患者具有较少的呼吸暂停，或者如果发生呼吸暂停，则能够在没有EEG唤醒的情况下重建气道。项目1-3通过识别导致动脉CO2升高的脑回路来实现第一个目标。这些项目旨在确定参与CO2唤醒的神经递质和受体，作为药理学操作的目标。项目4的重点是控制颏舌肌，最大的气道扩张。它将检查颏舌肌运动神经元的输入，这些神经元在睡眠期间抑制音调，这样我们就可以增加颏舌肌运动音调。项目5是一项人类研究，使用我们关于控制EEG唤醒和颏舌肌的假设来产生和测试OSA的新治疗方法。我们希望，随着我们在项目1-4中对这种大脑回路的了解更多，我们将在项目1-4中改进我们的治疗方法。 5.核心A组织的频繁会议也促进了这些项目之间的互动，包括所有研究者参加的每三周一次的研究者会议， 轮流介绍他们的进展情况，并听取同事的反馈意见，以进一步改进他们的工作;我们的内部或外部咨询委员会的年度会议，提供来自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分享了许多尖端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理学方法，通过该方法，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.