THE ROLE OF CYTOKINES IN SLEEPINESS AND SLEEP APNEA

描述（申请人摘要）：过度白天嗜睡（EDS）是一种 主要的公共卫生问题，部分原因是患有EDS的人 在工作中往往没有效率，更容易发生事故， 一般来说，他们在白天无法正常工作。EDS是一家 阻塞性睡眠呼吸暂停综合征的主要表现 (OSA)并且经常由没有睡眠呼吸暂停的肥胖个体报告。的 在这两种类型的个体中观察到的EDS的潜在机制并不 清楚我们最近已经证明，促炎和 疲劳诱导细胞因子、肿瘤坏死因子-α（TNF α）和 白细胞介素-6（IL-6），在单个血浆样品中测定， 患有EDS疾病的受试者。此外，在初步研究中， 表明这两种细胞因子在肥胖者中升高，与瘦的相比， 研究对象，睡眠障碍和肥胖都有助于 细胞因子升高。最近，我们发现白天血浆IL-6水平 通过睡眠剥夺实验诱导的EDS升高， 良好的夜间睡眠与降低白天的 健康的年轻人。有大量的文献表明， 促炎细胞因子在动物睡眠调节中的作用;然而， 细胞因子对人类睡眠的研究非常有限。根本 拟议研究要检验的假设是， 细胞因子TNF α和IL-6与EDS相关并可能促成EDS。我们 将通过确定的昼夜分泌模式来测试这一假设， 从表现出EDS相关的受试者获得的血浆中的TNF α和IL-6 阻塞性睡眠呼吸暂停综合征或肥胖此外，我们将确定夜间鼻CPAP是否 降低睡眠呼吸暂停患者白天血浆TNF α和IL-6浓度。在 此外，我们将在健康的年轻受试者中实验性地诱导EDS， 使用完全睡眠剥夺或一周的睡眠限制， 真实的生活情景，以确定模式之间的关系， 白天血浆TNF α和IL-6浓度以及白天嗜睡， 使用MPEG4进行客观测量。最后，我们将评估白天 健康受试者午睡对午睡后嗜睡和TNF α及IL-6的影响 分泌物在这些研究中，我们将使用一系列的实验技术 包括夜间多导睡眠描记术、MPEG 1、计算机化EEG、活动描记术， 24-小时血液采样、24小时核心体温记录和分析 TNF α和IL-6。这些研究将提供额外的 TNF α和IL-6在EDS中的作用的证据，并奠定了基础， 开发潜在的治疗干预措施。

DESCRIPTION (applicant's abstract): Excessive daytime sleepiness (EDS) is a major public health concern, in part because individuals suffering from EDS often are not productive at work, are more susceptible to accidents, and generally are unable to function normally during the day. EDS is one of the major manifestations of individuals suffering from obstructive sleep apnea (OSA) and is frequently reported by obese individuals without sleep apnea. The mechanisms underlying EDS observed in both types of these individuals are not clear. We have recently demonstrated that the pro-inflammatory and fatigue-inducing cytokines, tumor necrosis factor-alpha (TNFalpha) and interleukin-6 (IL-6), assayed in single plasma samples, are elevated in subjects with disorders of EDS. In addition, in preliminary studies, we demonstrated that these two cytokines are elevated in obese, compared to lean subjects, and that both sleep disturbance and obesity contribute to the cytokine elevation. More recently, we showed that daytime plasma levels of IL-6 are elevated in experimentally-induced EDS by the use of sleep deprivation and that a good night's sleep is associated with decreased daytime levels in healthy young subjects. There is a large literature implicating several pro-inflammatory cytokines in the regulation of sleep in animals; however, cytokine research on sleep in humans has been very limited. The fundamental hypothesis to be tested by the proposed studies is that the pro-inflammatory cytokines, TNFalpha and IL-6, are associated with and may contribute to EDS. We will test this hypothesis by determining the circadian secretory patterns of TNFalpha and IL-6 in plasma obtained from subjects that exhibit EDS associated with OSA or obesity. Also, we will determine whether nighttime nasal CPAP reduces daytime plasma TNFalpha and IL-6 concentrations in sleep apneics. In addition, we will experimentally induce EDS in healthy young subjects by the use of total sleep deprivation or one week of sleep restriction, which mimics real life-situations, to determine the relationship between the pattern of daytime plasma TNFalpha and IL-6 concentrations and daytime sleepiness as measured objectively using MSLT. Finally, we will assess the effects of daytime napping, in healthy subjects, on post-nap sleepiness and TNFalpha and IL-6 secretion. In these studies, we will use a series of experimental techniques including nighttime polysomnography, MSLT, computerized EEG, actigraphy, 24-hour blood sampling, 24-hour recording of core body temperature, and assays for TNFalpha and IL-6. These studies collectively will provide additional evidence for a role of TNFalpha and IL-6 in EDS and lay the foundation for the development of potential therapeutic interventions.