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，与西方社会日益普遍的肥胖有关。这是由于睡眠期间反复发作的上呼吸道阻塞。上呼吸道神经肌肉控制的潜在解剖学改变和/或紊乱被认为在阻塞性睡眠呼吸暂停的发病机制中起关键作用，肥胖也是这种疾病的潜在危险因素。该提案调查了肥胖与睡眠呼吸暂停之间的联系机制，并基于区域脂肪分布差异导致睡眠期间上气道功能障碍的概念。内脏和皮下脂肪的区域差异与可能影响上呼吸道通畅的神经机械控制的机械改变和CNS作用信号蛋白（脂肪因子）的不同特征相关。我们的主要假设是脂肪组织的分布、信号传导和基因表达的相对差异调节重度肥胖患者的上气道神经机械功能。这一假设是基于强有力的初步数据，暗示区域性肥胖在睡眠期间上呼吸道功能的调节。我们的数据表明，脂肪分布、脂肪因子和基因表达的显著差异可以保护或损害睡眠期间的上呼吸道通畅。将评估反映上气道机械负荷（被动Pcrit）和代偿性神经反应（deltaVimax和deltaEMGGG）的离散生理表型，以表征从健康到疾病的上气道功能障碍程度。新的手术减肥策略将被用来阐明区域脂肪分布，脂肪因子和基因表达对上气道神经机械控制的影响。在横断面（SA#1）和纵向人体研究（SA#2）中，我们将确定这些因素如何影响睡眠期间的上呼吸道功能。在补充的鼠类研究中，将采用独特的体重减轻干预措施来暗示控制上呼吸道功能的特定机械、体液和分子途径（SA#3）。该提案将阐明睡眠期间肥胖与上呼吸道功能障碍之间的机制和因果通路，并将提供疾病易感性和治疗反应的新型体液和分子预测因子。

DESCRIPTION (provided by applicant): Obstructive sleep apnea is a common disorder linked to the increasing prevalence of obesity in Western society. It is due to recurrent episodes of upper airway obstruction during sleep. Underlying anatomic alterations and/or disturbances in upper airway neuromuscular control are thought to play key roles in the pathogenesis of obstructive sleep apnea, as does obesity, a potent risk factor for this disorder. This proposal investigates the mechanisms linking obesity with sleep apnea, and is based on the concept that differences in regional fat distribution cause upper airway dysfunction during sleep. Regional differences in visceral and subcutaneous fat have been associated with mechanical alterations and distinct profiles of CNS-acting signaling proteins (adipokines) that may affect the neuromechanical control of upper airway patency. Our primary hypothesis is that relative differences in the distribution, signaling and gene expression of adipose tissue modulate upper airway neuromechanical function in severe obesity. This hypothesis is predicated on strong preliminary data implicating regional adiposity in the regulation of upper airway function during sleep. Our data indicate that striking differences in fat distribution, adipokines and gene expression can either protect or compromise upper airway patency during sleep. Discrete physiologic phenotypes reflecting upper airway mechanical loads (passive Pcrit) and compensatory neural responses (deltaVimax and deltaEMGGG) will be assessed to characterize the degree of upper airway dysfunction across the spectrum from health to disease. Novel surgical weight loss strategies will be utilized to elucidate the effects of regional fat distribution, adipokines and gene expression on upper airway neuromechanical control. In cross-sectional (SA#1) and longitudinal human studies (SA#2), we will establish how these factors impact on upper airway function during sleep. In complementary murine studies, unique weight loss interventions will be employed to implicate specific mechanical, humoral and molecular pathways controlling upper airway function (SA#3). This proposal will elucidate the mechanisms and causal pathways linking obesity with upper airway dysfunction during sleep, and will provide novel humoral and molecular predictors of disease susceptibility and treatment responses.