Intermittent Hypoxia: Mechanisms of Hypersomnolence

间歇性缺氧：嗜睡的机制

• 批准号: 7392402
• 负责人: SIGRID C VEASEY
• 金额: $ 38.23万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7392402
• 关键词: Adult; American; Angiotensin II; Angiotensinogen; Angiotensins; Apoptosis; Behavioral; Biological Assay; Brain; Brain region; Cell Count; Cell Fractionation; Cells; Count; Depth; Development; Enzyme Inhibition; Enzyme-Linked Immunosorbent Assay; Enzymes; Event; Exposure to; Hypersomnolence; Hypoxia; Immunohistochemistry; Impairment; Individual; Injury; Lasers; Modeling; Molecular Target; Mus; NADPH Oxidase; Nature; Neurocognitive; Neurons; Obstructive Sleep Apnea; Pattern; Persons; Polymerase Chain Reaction; Population; Predisposition; Prevention; Prosencephalon; Protein Overexpression; Receptor Activation; Receptor Inhibition; Recovery; Research Personnel; Residual state; Resistance; Signal Transduction; Sleep; Sleep Apnea Syndromes; Source; Superoxides; Testing; Time; Transgenic Model; Transgenic Organisms; Up-Regulation; Wakefulness; Work; caspase-3; clinically significant; enzyme activity; field study; immunoreactivity; injured; innovation; locus ceruleus structure; mouse model; nerve injury; neurobehavioral; neuron loss; noradrenergic; prevent; programs; receptor; receptor function; relating to nervous system; response

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.

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，但仍会有持续性的睡眠症。我们发现，暴露在长期间歇性低氧(LTIH)下，在成年小鼠中模拟严重阻塞性睡眠呼吸暂停的氧合作用，会导致持久的睡眠亢进和氧化损伤，以选择觉醒活跃的神经组。在初步研究中，我们发现LTIH诱导蓝斑去甲肾上腺素能神经元的凋亡和丢失。我们现在应该扩展这一点来确定LTIH主要觉醒促进组的损伤的性质和程度：食欲素能、组胺能和多巴胺能觉醒活性神经元，我们应该确定这种损伤是否在长期恢复中是可逆的(目标1)。我们最近发现，NADPH氧化酶是觉醒活动区氧化损伤的主要来源，而在整个LTIH中，NADPH氧化酶的减少可以防止高睡眠。现在重要的是确定NADPH氧化酶是否在LTIH损伤相关的细胞凋亡和神经丢失中起重要作用。我们建议确定上述觉醒活动组中NADPH氧化酶的激活是否预测LTIH神经丢失的易感性，我们建议使用整个LTIH中缺乏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主要觉醒控制神经元组的细胞凋亡和神经丢失(目标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，并且发现易感性增加的神经组主要是具有血管紧张素1A受体(AT1A)免疫反应的神经元，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(儿茶酚胺能觉醒神经元)将是最容易受到LTIH影响的神经元。我们进一步假设，转基因血管紧张素的缺失和药物抑制将阻止NADPH氧化酶的激活和睡眠亢进，以及觉醒活性神经元的凋亡和丧失。为了验证这一假设，我们建议通过转基因和药物抑制AT1a受体功能的小鼠来检测觉醒活性组中NADPH氧化酶的激活，并确定是否可以在相同的模型中预防睡眠过度和神经元丢失并逆转(目标3)。总之，这些研究将展示LTIH模拟睡眠呼吸暂停氧合损伤神经元的主要机制，同时，这项工作将揭示药理学途径，以测试治疗和预防阻塞性睡眠呼吸暂停的神经认知障碍。