Oxidative stress in a murine model of sleep apnea

睡眠呼吸暂停小鼠模型中的氧化应激

• 批准号: 7462860
• 负责人: David Gozal
• 金额: $ 33.3万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2009-02-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7462860
• 关键词: Address; Adult; Affect; Animal Model; Apoptosis; Arousal; Behavioral; Breathing; CREB1 gene; Carbohydrates; Cardiovascular system; Chronic; Cognitive; Cognitive deficits; Complex; Condition; Consumption; Development; Diet; Dinoprostone; Disease; Elements; Environmental Risk Factor; Enzyme Activation; Exhibits; Exposure to; F2-Isoprostanes; Fatty acid glycerol esters; Functional disorder; Gene Proteins; Genetic; Hippocampus (Brain); Human; Hypoxia; Impaired cognition; Individual; Inflammation; Learning; Light; Malondialdehyde; Medical; Memory; Memory impairment; Modeling; Modification; Molecular; Morbidity - disease rate; Mus; NAD(P)H oxidase; NADP; NADPH Oxidase; Nerve Degeneration; Neurocognitive; Neurodegenerative Disorders; Neuronal Injury; Neurons; Numbers; OSA; Obesity; Obstructive Sleep Apnea; Outcome; Oxidative Stress; PTGS2 gene; Pathogenesis; Pathway interactions; Patients; Pattern; Phosphorylation; Predictive Value; Predisposition; Prevalence; Production; Public Health; Recurrence; Risk Factors; Rodent; Rodent Model; Role; Severity of illness; Sleep; Sleep Apnea Syndromes; Sleep Fragmentations; Societies; Source; Superoxides; Testing; United States; Variant; Water; acetovanillone; airway obstruction; basal forebrain; day; dentate gyrus; functional loss; gray matter; immunocytochemistry; inhibitor/antagonist; insight; male; morris water maze; mouse model; neurobehavioral; neutrophil cytosol factor 67K; prevent; protein expression; response; sugar

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.

描述(申请人提供)：阻塞性睡眠呼吸暂停综合征(OSAS)是最严重的睡眠呼吸紊乱(SDB)形式，是一种以反复发作间歇性低氧(IH)为特征的疾病，经常导致人类严重的神经认知疾病。啮齿动物模型已经证明，IH与行为学习和记忆障碍有关，而行为学习和记忆障碍之前是海马体和皮质的神经退行性变化。NADPH氧化酶是超氧阴离子自由基的主要来源，它的激活可能是IH诱导的许多氧化修饰的基础，并有助于IH的行为和神经元后果。最近的证据也表明，摄入高脂肪和高糖的饮食是肥胖的主要原因，不仅增加了神经元损伤的易感性，而且增加了NADPH氧化酶的激活，这表明饮食和IH可能通过一个共同的途径增加氧化应激。鉴于肥胖是OSAS的主要危险因素，确定与疾病相关的神经认知疾病的潜在因素是当务之急。为了验证高血压和饮食(肥胖的主要环境原因)调节神经元对高血压易感性的假说，采用Morris水迷宫任务范式、NADPH氧化酶基因和蛋白表达的变化、氧化应激标志物和细胞凋亡，在成年小鼠模型上检验了三个主要的特异性目标：(1)遗传缺乏NADPH氧化酶活性(gp91Phox-/-小鼠)对行为和神经元对14天间歇性日间低氧(IH)敏感性的影响；(2)给予NADPH氧化酶复合体组装抑制剂apocynin对14天间歇性日间低氧(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的行为和神经元敏感性，以及这些缺陷是否可以通过缺乏NADPH活性(gp91Phox-/-小鼠)和/或Apoynin(NADPH氧化酶复合体组装抑制物)来预防。这些研究将深入了解IH对神经元功能影响的潜在机制，以及环境因素如何影响OSAS相关认知缺陷的发病机制。公共卫生相关性：阻塞性睡眠呼吸暂停综合征(OSAS)是睡眠障碍呼吸(SDB)最严重的形式，经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变异性表明，内在因素(即基因决定的)或外在因素(即环境获得性因素)都改变了睡眠呼吸暂停的行为易感性。本申请中的研究将利用OSAS患者夜间呼吸模式的小鼠模型，不仅提供关于这种功能障碍潜在的细胞和分子机制的信息，而且还提供OSAS的主要外部因素肥胖可能改变这种反应的方式。鉴于阻塞性睡眠呼吸暂停综合征和肥胖症在我们的社会中日益流行，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。