OBESITY AND NEURAL CONTROL IN SLEEP-DISORDERED BREATHING

描述（由申请人提供）：睡眠呼吸障碍主要表现为睡眠时部分或全部上呼吸道阻塞。睡眠呼吸障碍最常见的形式是阻塞性睡眠呼吸暂停，由于上呼吸道在睡眠状态开始时反复塌陷。与睡眠呼吸暂停有关的主要危险因素是肥胖、男性和年龄较大。目前，我们的总体假设是肥胖改变了机械特性和代偿神经肌肉反应，导致上气道阻塞。根据我们最近的研究结果，我们证明肥胖与上呼吸道机械特性（被动Pcrit）的改变有关，这种改变被代偿性上呼吸道神经反应（主动Pcrit）所抵消。代偿性神经肌肉反应的丧失导致阻塞性睡眠呼吸暂停。在Specific Aim 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、瘦素增加和年龄较小与代偿性神经肌肉反应增加有关，而男性、中枢性肥胖、瘦素减少和年龄较大与代偿性神经肌肉反应减弱有关。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，我们假设体重减轻会降低男性和女性阻塞性睡眠呼吸暂停患者的被动Pcrit和/或恢复代偿神经肌肉反应。本研究旨在阐明阻塞性睡眠呼吸暂停发展的病理生理基础。新的生理技术已经在睡眠中发展起来，允许上呼吸道控制的机械和神经调节的分配。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，从而潜在地为治疗睡眠呼吸障碍提供了新的方法。

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.