Intermittent Hypoxia: Mechanisms of Hypersomnolence

描述（申请人提供）：超过800万美国成年人患有阻塞性睡眠呼吸暂停综合征。这些人中的许多人尽管接受了治疗，但仍会持续嗜睡。我们已经发现，暴露于长期间歇性缺氧（LTIH），模拟严重阻塞性睡眠呼吸暂停的氧合，在成年小鼠中导致持久的嗜睡和氧化损伤，以选择唤醒活跃的神经组。在初步研究中，我们发现LTIH诱导去甲肾上腺素能蓝斑神经元的凋亡和丢失。我们现在应该扩展这一点，以确定主要促觉醒群体中LTIH损伤的性质和程度：食欲素能、组胺能和多巴胺能觉醒活性神经元，并且我们应该确定这种损伤是否可以通过长期恢复而可逆（目标1）。我们最近发现NADPH氧化酶是唤醒活跃区氧化损伤的主要来源，整个LTIH中还原的NADPH氧化酶可防止嗜睡。现在重要的是确定NADPH氧化酶是否是与LTIH损伤相关的细胞凋亡和神经损失所必需的。我们建议确定上述唤醒活性组中的NADPH氧化酶激活是否预测对LTIH神经损失的易感性，并且我们建议使用在整个LTIH中不存在NADPH氧化酶激活的转基因和药理学模型来确定我们是否可以防止唤醒控制神经元的主要组中的细胞凋亡和神经损失（目的2）。下一步是确定LTIH激活NADPH氧化酶的机制。在神经元中发现了NADPH氧化酶，并且发现具有增加的易感性的神经组主要是具有血管紧张素1A受体（AT1A）免疫反应性的神经元，我们假设LTIH导致HIF-1a激活的血管紧张素合成，并且具有AT1A受体和NADPH氧化酶的神经元（儿茶酚胺能唤醒神经元）将是对LTIH最脆弱的神经元。我们进一步假设，转基因缺乏和药理学抑制血管紧张素将防止NADPH氧化酶激活和嗜睡和凋亡和觉醒活性神经元的损失。为了验证这一假设，我们建议在具有AT1A受体功能的转基因和药理学抑制的小鼠中检查唤醒活性组中的NADPH氧化酶活化，并且我们将确定在相同模型中是否可以预防和逆转嗜睡和神经元损失（目的3）。总的来说，这些研究将证明LTIH建模睡眠呼吸暂停氧合损伤神经元的主要机制，同时，这项工作将揭示测试治疗和预防阻塞性睡眠呼吸暂停神经认知障碍的药理学途径。

DESCRIPTION (provided by applicant): Over 8 million adult Americans have obstructive sleep apnea syndrome. Many of these individuals will have persistent hypersomnolence despite therapy. We have found that exposure to long-term intermittent hypoxia (LTIH), modeling oxygenation in severe obstructive sleep apnea, in adult mice results in lasting hypersomnolence and oxidative injury to select wake-active neural groups. In preliminary studies, we are finding LTIH-induces apoptosis and loss of noradrenergic locus coeruleus neurons. We should now extend this to determine the nature and extent of LTIH injury in major wake-promoting groups: orexinergic, histaminergic and dopaminergic wake-active neurons, and we should determine if this injury is reversible with long-term recovery (Aim 1). We have recently shown that NADPH oxidase is a major source of oxidative injury in wake-active regions and that reduced NADPH oxidase throughout LTIH prevents hypersomnolence. It is now important to determine if NADPH oxidase is essential for the apoptosis and neural loss associated with LTIH injury. We propose to determine if NADPH oxidase activation in the above wake-active groups predicts susceptibility to LTIH neural loss, and we propose to use transgenic and pharmacological models of absent NADPH oxidase activation throughout LTIH to determine whether we can prevent apoptosis and neural loss in major groups of wake-control neurons (Aim 2). A next step is to determine the mechanism through which LTIH activates NADPH oxidase. Having found NADPH oxidase in neurons and having found that the neural groups with increased susceptibility are largely neurons with angiotensin 1A receptor (AT1A) immunoreactivity, we hypothesize that LTIH results in HIF-1a activated angiotensin synthesis, and that neurons with both AT1A receptors and NADPH oxidase (catecholaminergic wake neurons) will be the neurons most vulnerable to LTIH. We further hypothesize that transgenic absence and pharmacological inhibition of angiotensin will prevent NADPH oxidase activation and hypersomnolence and apoptosis and loss of wake-active neurons. To test this hypothesis, we propose to examine NADPH oxidase activation in wake-active groups in mice with transgenic and pharmacological inhibition of AT1A receptor function and we will determine if the hypersomnolence and neuron loss may be prevented, and reversed in the same models (Aim 3). Collectively, these studies will demonstrate major mechanisms through which LTIH modeling sleep apnea oxygenation injures neurons and at the same time, this work will unveil pharmacological avenues to test for the treatment and prevention of neurocognitive impairments in obstructive sleep apnea.