Mechanisms of Sleep Apnea in Severe Obesity

描述（由申请人提供）：阻塞性睡眠呼吸暂停是一种常见的疾病，其患病率与西方社会的肥胖流行病有关。睡眠呼吸暂停是由于睡眠期间上呼吸道阻塞的反复发作，其由睡眠期间上呼吸道可接受性升高引起。目前的证据表明，上呼吸道神经肌肉控制的解剖学改变和障碍在阻塞性睡眠呼吸暂停的发病机制中起着关键作用。肥胖，特别是中枢性肥胖是睡眠呼吸暂停的潜在危险因素。我们的主要假设是，肥胖症的代谢和炎症失调导致睡眠期间上呼吸道机械和神经肌肉控制的特定缺陷。为了解决这一假设，人类和小鼠模型将探讨肥胖症睡眠期间上气道功能障碍的机制。将实施戏剧性的手术减肥和特定的夜间干预，以阐明导致睡眠期间上气道功能障碍的特定生理、代谢和炎症机制（SA 1和2）。补充小鼠实验，建议建立特定的脂肪细胞因子和代谢途径的发病机制，上呼吸道阻塞在睡眠（SA 3）。一个跨学科的团队将利用该项目的科学和机构资源：（1）定义睡眠呼吸暂停易感性的不同生理，代谢和炎症介质，（2）为诊断和治疗目的的新生物标志物和途径奠定基础。 公共卫生相关性：阻塞性睡眠呼吸暂停是一种常见的疾病，其发病率和死亡率与西方社会的肥胖流行有关。该建议针对肥胖症患者睡眠呼吸暂停的潜在生理、代谢和炎症原因。它有望揭示这种疾病的早期诊断和治疗的新策略。

DESCRIPTION (provided by applicant): Obstructive sleep apnea is a common disorder whose prevalence is linked to an epidemic of obesity in Western society. Sleep apnea is due to recurrent episodes of upper airway obstruction during sleep that are caused by elevations in upper airway collapsibility during sleep. Current evidence indicates that anatomic alterations and disturbances in upper airway neuromuscular control play key roles in the pathogenesis of obstructive sleep apnea. Obesity and particularly central adiposity are potent risk factors for sleep apnea. Our primary hypothesis is that metabolic and inflammatory dysregulation in obesity produce specific defects in upper airway mechanical and neuromuscular control during sleep. To address this hypothesis, human and murine models will be probed to characterize the mechanisms of upper airway dysfunction during sleep in obesity. Dramatic surgical weight loss and specific nocturnal interventions will be implemented to elucidate specific physiologic, metabolic and inflammatory mechanisms causing upper airway dysfunction during sleep (SA 1 & 2). Complementary murine experiments are proposed to establish specific adipocytokines and metabolic pathways in the pathogenesis of upper airway obstruction during sleep (SA3). An inter-disciplinary team will leverage scientific and institutional resources in this project to: (1) define distinct physiologic, metabolic and inflammatory mediators of sleep apnea susceptibility, and (2) lay the groundwork for targeting novel biomarkers and pathways for diagnostic and therapeutic purposes. PUBLIC HEALTH RELEVANCE: Obstructive sleep apnea is a common disorder associated with substantial morbidity and mortality whose prevalence is linked to an epidemic of obesity in Western society. This proposal addresses the underlying physiologic, metabolic and inflammatory causes of sleep apnea in obesity. It promises to uncover new strategies for early diagnosis and treatment of this disorder.