OBESITY AND NEURAL CONTROL IN SLEEP-DISORDERED BREATHING

描述（由申请人提供）：睡眠呼吸障碍的主要特征是睡眠期间部分或全部上气道阻塞。睡眠呼吸障碍最常见的形式是阻塞性睡眠呼吸暂停，这是由于睡眠状态开始时上气道反复塌陷造成的。与睡眠呼吸暂停相关的主要危险因素是肥胖、男性和老年。目前，我们的总体假设是肥胖改变了机械特性和代偿性神经肌肉反应，导致上气道阻塞。基于我们最近的研究结果，我们证明肥胖与上气道的机械特性（被动Pcrit）的改变相关，上气道的机械特性（被动Pcrit）被代偿性上气道神经反应（主动Pcrit）抵消。代偿性神经肌肉反应的丧失导致阻塞性睡眠呼吸暂停。在具体目标1中，我们将探讨性别、肥胖和年龄对阻塞性睡眠呼吸暂停患者和正常人的影响。我们的初步数据表明，女性，外周性肥胖，瘦素增加和年轻的年龄与增加的代偿性神经肌肉反应，而男性，中心性肥胖，瘦素减少和老年与钝化的代偿性反应。在具体目标2中，我们将确定颏舌肌的作用，以及是否需要其他肌肉的共同激活来维持上气道通畅。在具体目标3中，我们假设体重减轻将降低阻塞性睡眠呼吸暂停男性和女性的被动Pcrit和/或恢复代偿性神经肌肉反应。这些研究旨在阐明阻塞性睡眠呼吸暂停的病理生理基础。新型生理技术在睡眠期间被开发出来，可以区分上呼吸道控制的机械和神经调节。这些研究还提供了对上呼吸道功能的神经体液调节的见解，从而为治疗睡眠呼吸障碍提供了潜在的新方法。

DESCRIPTION (provided by applicant): Sleep-disordered breathing is characterized primarily by partial or total upper airway obstruction during sleep. The most common form of sleep-disordered breathing is obstructive sleep apnea due to recurrent collapse of the upper airway with the onset of sleep state. The major risk factors associated with the development of sleep apnea are obesity, male gender, and older age. Currently, our overall hypothesis is that obesity alters both mechanical properties and compensatory neuromuscular responses leading to upper airway obstruction. Based on our most recent findings, we demonstrate that obesity is associated with alterations in the mechanical properties (passive Pcrit) of the upper airway that are counterbalanced by compensatory upper airway neural responses (active Pcrit). Loss of the compensatory neuromuscular responses leads to obstructive-sleep apnea. In Specific Aim 1, we will explore the effects of gender, obesity and age in patients with obstructive sleep apnea and normal individuals. Our preliminary data suggest that female gender, peripheral adiposity, increased leptin and younger age are associated with increased compensatory neuromuscular responses, while male gender, central adiposity, decreased leptin and older age are associated with blunted compensatory responses. In Specific Aim 2, we will determine the role of the genioglossus muscle and whether co-activation of other muscles is required for the maintenance of upper airway patency. In Specific Aim 3, we hypothesize that weight reduction will lower the passive Pcrit and/or restore the compensatory neuromuscular responses in both men and women with obstructive sleep apnea. The proposed studies are designed to elucidate the pathophysiologic basis for the development of obstructive sleep apnea. Novel physiologic techniques have been developed during sleep and allow partitioning of the mechanical and neural regulation of upper airway control. The studies also provide insights into the neurohumoral regulation of upper airway function, and thus potentially new approaches to the treatment for sleep-disordered breathing.