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，与严重的心血管和神经疾病有关。最常见和最令人担忧的神经行为后遗症之一是接受阻塞性睡眠呼吸暂停治疗的患者残留的嗜睡。在之前的获奖期间，我们建立了模拟严重睡眠呼吸暂停(长期间歇性低氧，LTIH)的氧合模式，导致不可逆转的觉醒损伤和儿茶酚胺能觉醒神经元的损伤。此外，在之前的获奖期间，我们发现NADPH氧化酶(NOX2)是神经元损伤和细胞凋亡的关键来源。下一个重要的步骤是确定LTIH对儿茶酚胺能觉醒神经元功能的直接影响，并确定NOX2是否参与LTIH对觉醒神经元功能的影响(目标1)。LTIH在细胞培养中的损伤机制超出了NOX2的激活范围，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LTIH损伤，一条可以扩大的途径最终可以在临床上预防或治疗损伤。SIRT1是一种氧化还原敏感的脱乙酰酶，它执行一种全面的抗氧化反应，包括上调抗氧化酶，优化线粒体的结构和数量，以减少线粒体超氧化物的产生。最近，我们在觉醒神经元中发现了SIRT1，并在常氧条件下确立了SIRT1在觉醒神经元中的重要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是否损害SIRT1的激活，以及SIRT1的减少是否加剧了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觉醒神经元功能和觉醒的影响外，我们准备开始将我们的发现转化为探索转基因增强SIRT1活性是否可以预防或部分逆转LTIH觉醒神经元损伤和受损的觉醒(目标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).