Intermittent Hypoxia: Mechanisms of Hypersomnolence

描述（由申请人提供）：阻塞性睡眠呼吸暂停是一种常见的疾病，与显著的心血管和神经系统发病率相关。阻塞性睡眠呼吸暂停综合征患者最常见和最令人不安的神经行为后遗症之一是残余嗜睡。在上一个奖项期间，我们建立了模拟严重睡眠呼吸暂停（长期间歇性缺氧，LTIH）的氧合模式，导致不可逆的觉醒障碍和儿茶酚胺能唤醒神经元损伤。此外，在前一个奖项期间，我们确定NADPH氧化酶（Nox 2）作为神经元损伤和凋亡的关键来源。下一个重要步骤是建立LTIH对儿茶酚胺能唤醒神经元功能的直接影响，并建立Nox 2是否有助于LTIH对唤醒神经元功能的影响（目的1）。细胞培养中的LTIH损伤机制超出了Nox 2活化，包括线粒体损伤和超氧化物歧化酶活性降低。我们已经开始探索内源性保护途径来对抗所有的LTIH损伤，最终可以增强这种保护途径来预防或治疗临床损伤。SIRT1是一种氧化还原敏感的脱乙酰酶，其执行全面的抗氧化反应，包括上调抗氧化酶和优化线粒体构型和数量以减少线粒体超氧化物的产生。最近，我们在清醒神经元中鉴定了SIRT1，并在常氧条件下建立了SIRT1在清醒神经元中的关键功能和神经保护作用。下一步是将这些发现与我们的LTIH工作相结合，并确定LTIH是否会损害SIRT 1的激活，以及SIRT 1的减少是否会加剧LTIH的损伤和行为影响（目标2）。除了研究SIRT1激活不足对儿茶酚胺能唤醒神经元功能和觉醒的影响外，我们准备开始转化我们的研究结果，以探索SIRT1活性的转基因增强是否可以预防或部分逆转LTIH中的唤醒神经元损伤和觉醒受损（目的3）。

DESCRIPTION (provided by applicant): Obstructive sleep apnea is a prevalent disorder associated with significant cardiovascular and neurological morbidity. One of the most common and troubling neurobehavioral sequelae is residual sleepiness in patients treated for obstructive sleep apnea. During the previous award period, we established that oxygenation patterns modeling severe sleep apnea (long-term intermittent hypoxia, LTIH) result in irreversible wake impairments and injury to catecholaminergic wake neurons. Also, in the previous award period we identified NADPH oxidase (Nox2) as a key source of neuronal injury and apoptosis. A next important step is to establish direct effects of LTIH on the function of catecholaminergic wake neurons and to establish whether Nox2 contributes to LTIH effects on wake neuron function (Aim 1). LTIH mechanisms of injury in cell culture extend beyond Nox2 activation to include mitochondrial injury and reduced superoxide dismutase activity. We have begun to explore endogenous protective pathways to counter all LTIH injuries, one that could be augmented to prevent or treat injuries clinically, ultimately. SIRT1 is a redox sensitive deacetylase that executes a comprehensive anti-oxidant response, including up-regulation of anti-oxidant enzymes and optimization of mitochondrial configuration and number to reduce mitochondrial superoxide production. Recently, we identified SIRT1 in wake neurons and established critical functional and neuroprotectant roles for SIRT1 in wake neurons under normoxic conditions. A next step is to integrate these findings with our LTIH work and determine whether LTIH impairs the SIRT1 activation and whether reduced SIRT1 accentuates injury and behavioral effects of LTIH (Aim 2). In addition to examining the impact of insufficient SIRT1 activation on catecholaminergic wake neuron function and wakefulness, we are poised to begin translating our findings to explore whether transgenic augmentation of SIRT1 activity can prevent or partially reverse wake neuron injuries and impaired wakefulness in LTIH (Aim 3).