Oxidative stress in a murine model of sleep apnea

描述（由申请人提供）：阻塞性睡眠呼吸暂停综合征（OSAS）是睡眠呼吸障碍（SDB）的最严重形式，是一种以反复发作的间歇性缺氧（IH）为特征的疾病，经常导致人类的大量神经认知疾病。啮齿动物模型已经证明IH与行为学习和记忆缺陷相关，这些缺陷之前是海马和皮质中的神经退行性变化。NADPH氧化酶是超氧自由基的主要来源，其激活可能是许多IH诱导的氧化修饰的基础，并有助于IH的行为和神经后果。最近的证据还表明，高脂肪和高糖饮食的消费，肥胖的主要原因，不仅增加神经元损伤的易感性，但增加NADPH氧化酶的激活，这表明饮食和IH可能通过共同的途径增加氧化应激。鉴于肥胖是OSAS的主要危险因素，因此必须确定导致与疾病相关的神经认知发病率的潜在因素。为了检验IH和饮食（肥胖的主要环境原因）调节神经元对IH的易感性的假设，将在成年小鼠模型中使用Morris水迷宫任务范例、NADPH氧化酶基因和蛋白质表达的变化、氧化应激的标志物和细胞凋亡来检查三个主要的具体目标，如下所示：（1）NADPH氧化酶活性遗传缺失的影响（gp 91 phox-/-小鼠）对14天间歇性日间缺氧（IH）的行为和神经元易感性的影响;（2）给予NADPH氧化酶复合物组装抑制剂夹竹桃素（apocynin）对14天间歇性日间缺氧（IH）的行为和神经元敏感性的影响;（3）确定长期高脂肪/精制碳水化合物（HFRC）饮食是否增加成年雄性小鼠对IH的行为和神经元易感性，以及这些缺陷是否通过缺乏NADPH活性（gp 91 phox-/-小鼠）和/或夹竹桃苷（一种NADPH氧化酶复合物组装的抑制剂）来预防。这些研究将为深入了解IH对神经元功能影响的潜在机制以及环境因素影响OSA相关认知缺陷发病机制的方式提供帮助。阻塞性睡眠呼吸暂停综合征（OSAS）是睡眠呼吸障碍（SDB）中最严重的一种，通常与人类的认知缺陷有关，目前估计仅在美国就有多达1800万人受到影响。睡眠呼吸暂停患者神经行为结果的显著差异表明，遗传决定的）或外源的（即，环境获得的）因素改变了对睡眠呼吸暂停的行为易感性。本申请中的研究将利用OSAS患者的夜间呼吸模式的小鼠模型，不仅提供关于这种功能障碍的潜在细胞和分子机制的信息，而且还提供OSAS的主要外在因素肥胖可以改变这种反应的方式。鉴于OSAS和肥胖在我们社会中的流行率越来越高，因此必须确定导致与疾病相关的不良行为结果的潜在因素。

DESCRIPTION (provided by applicant): Obstructive sleep apnea syndrome (OSAS), the most severe form of sleep disordered breathing (SDB), is a condition characterized by repeated episodes of intermittent hypoxia (IH) that frequently imposes substantial neurocognitive morbidities in humans. Rodent models have demonstrated that IH is associated with behavioral learning and memory deficits that are preceded by neurodegenerative changes in the hippocampus and cortex. Activation of the enzyme NADPH oxidase, a major source of superoxide radicals, may underlie many of the IH-induced oxidative modifications and contribute to the behavioral and neuronal consequences of IH. Recent evidence also indicates that consumptions of a diet high in fat and sugar, a major cause of obesity, not only enhances susceptibility to neuronal injury but increases activation of NADPH oxidase, suggesting that diet and IH may increase oxidative stress through a common pathway. Given that the obesity is a major risk factor for OSAS, it is imperative to identify the underlying factors that contribute to the neurocognitive morbidities associated with the disease implications. To test the hypothesis that IH and diet, a primary environmental cause of obesity, modulate neuronal susceptibility to IH, three major specific aims will be examined in an adult mouse model using as using Morris water maze task paradigms, changes in NADPH oxidase gene and protein expression, markers of oxidative stress, and apoptosis as follows: (1) The effect of genetic absence of NADPH oxidase activity (gp91phox-/- mice) on the behavioral and neuronal susceptibility to 14 days of intermittent daytime hypoxia (IH); (2) The effect of administration of apocynin, an inhibitor of assembly of the NADPH oxidase complex, on the behavioral and neuronal susceptibility to 14 days of intermittent daytime hypoxia (IH); (3) To determine if a long-term high fat/refined carbohydrate (HFRC) diet increases the behavioral and neuronal susceptibility of adult male mice to IH, and whether these deficits are prevented by the absence of NADPH activity (gp91phox-/- mice), and/or apocynin, an inhibitor of assembly of the NADPH oxidase complex. These studies will provide insight into the potential mechanisms which underlie the effects of IH on neuronal function, as well as the manner whereby environmental factors influence the pathogenesis of OSAS-associated cognitive deficits. PUBLIC HEALTH RELEVANCE:Obstructive sleep apnea syndrome (OSAS), the most severe form of sleep disordered breathing (SDB), is frequently associated with cognitive deficits in humans and is currently estimated to affect as many as 18 million individuals in the United States alone. Substantial variability in the neurobehavioral outcomes of patients with sleep apnea suggest that both intrinsic (i.e., genetically-determined) or extrinsic (i.e., environmentally acquired) elements modify the behavioral susceptibility to sleep apnea. The studies in the present application will utilize a mouse model of the nocturnal breathing patterns of OSAS patients to not only provide information as to the potential cellular and molecular mechanisms underlying such dysfunction, but also the manner in which a primary extrinsic factor for OSAS, obesity, may modify such responses. Given the increasing prevalence of both OSAS and obesity in our society, it is therefore imperative to identify the underlying factors that contribute to the adverse behavioral outcomes associated with the disease.