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

基本信息

批准号：
7637856
负责人：
David Gozal
金额：
$ 39万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7637856
关键词：
Address Adult Affect Animal Model Apoptosis Arousal Behavioral Breathing CREB1 gene Carbohydrates Cardiovascular system Chronic Cognitive Cognitive deficits Complex 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 NADP NADPH Oxidase Nerve Degeneration Neurocognitive Neurodegenerative Disorders Neuronal Injury Neurons Obesity Obstructive Sleep Apnea Outcome Oxidases Oxidative Stress PTGS2 gene Pathogenesis Pathway interactions Patients Pattern Phosphorylation Predictive Value Predisposition Prevalence Production 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 dentate gyrus functional loss gray matter immunocytochemistry inhibitor/antagonist insight male morris water maze mouse model neurobehavioral neutrophil cytosol factor 67K prevent protein expression public health relevance response sugar

项目摘要

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（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 与行为学习和记忆缺陷有关，而行为学习和记忆缺陷会导致海马体和皮质的神经退行性变化。 NADPH 氧化酶（超氧自由基的主要来源）的激活可能是许多 IH 诱导的氧化修饰的基础，并导致 IH 的行为和神经元后果。最近的证据还表明，摄入高脂肪和高糖饮食（肥胖的主要原因）不仅会增加对神经元损伤的易感性，还会增加 NADPH 氧化酶的激活，这表明饮食和 IH 可能通过共同途径增加氧化应激。鉴于肥胖是 OSAS 的主要危险因素，因此必须确定导致与疾病影响相关的神经认知发病的潜在因素。为了检验 IH 和饮食（肥胖的主要环境原因）调节神经元对 IH 敏感性的假设，将在成年小鼠模型中使用 Morris 水迷宫任务范式、NADPH 氧化酶基因和蛋白质的变化来检查三个主要具体目标表达、氧化应激标志物和细胞凋亡如下： (1) NADPH 氧化酶活性遗传缺失（gp91phox-/- 小鼠）对 14 的行为和神经元易感性的影响白天间歇性缺氧（IH）天数； (2) 施用夹竹桃麻素（一种 NADPH 氧化酶复合物组装抑制剂）对 14 天间歇性白天缺氧（IH）的行为和神经元易感性的影响； (3) 确定长期高脂肪/精制碳水化合物 (HFRC) 饮食是否会增加成年雄性小鼠对 IH 的行为和神经元易感性，以及这些缺陷是否可以通过缺乏 NADPH 活性来预防（gp91phox-/- 小鼠））和/或夹竹桃麻素（NADPH 氧化酶复合物组装抑制剂）。这些研究将深入了解 IH 对神经元功能影响的潜在机制，以及环境因素影响 OSAS 相关认知缺陷发病机制的方式。公共健康相关性：阻塞性睡眠呼吸暂停综合征 (OSAS) 是最严重的睡眠呼吸障碍 (SDB) 形式，通常与人类认知缺陷相关，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着差异表明，内在（即遗传决定）或外在（即环境获得）因素都会改变对睡眠呼吸暂停的行为易感性。本申请中的研究将利用 OSAS 患者夜间呼吸模式的小鼠模型，不仅提供有关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的方式。，可以修改此类响应。鉴于 OSAS 和肥胖在我们社会中的患病率日益增加，因此必须确定导致与该疾病相关的不良行为结果的潜在因素。