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与心血管和神经系统疾病相关的普遍疾病。其中一个最常见的和令人不安的神经行为后遗症是在治疗阻塞性睡眠呼吸暂停患者的残余嗜睡。在之前的研究期间，我们证实了模拟严重睡眠呼吸暂停（长期间歇性缺氧，LTIH）的氧合模式会导致不可逆的觉醒障碍和儿茶酚胺能觉醒神经元的损伤。此外，在之前的研究中，我们发现NADPH氧化酶（Nox2）是神经元损伤和凋亡的关键来源。下一个重要步骤是确定LTIH对儿茶酚胺能觉醒神经元功能的直接影响，并确定Nox2是否有助于LTIH对觉醒神经元功能的影响（Aim 1）。细胞培养中的LTIH损伤机制不仅包括Nox2激活，还包括线粒体损伤和超氧化物歧化酶活性降低。我们已经开始探索对抗所有LTIH损伤的内源性保护途径，最终可以增强到临床预防或治疗损伤。SIRT1是一种氧化还原敏感的去乙酰化酶，它执行全面的抗氧化反应，包括上调抗氧化酶和优化线粒体结构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发现了SIRT1，并在正常环境下确定了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工作结合起来，确定LTIH是否会损害SIRT1的激活，以及SIRT1的减少是否会加重LTIH的损伤和行为影响（目的2）。除了研究SIRT1激活不足对儿茶酚胺能觉醒神经元功能和觉醒的影响外，我们还准备开始翻译我们的研究结果，以探索转基因SIRT1活性的增强是否可以预防或部分逆转LTIH的觉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).