OBESITY AND NEURAL CONTROL IN SLEEP DISORDERED BREATHING

描述（申请人摘要）：睡眠呼吸障碍的特征是 上呼吸道阻塞和睡眠时换气不足。阻塞性睡眠 呼吸暂停是睡眠呼吸障碍的最常见形式， 睡眠期间上呼吸道反复塌陷。的主要危险因素 睡眠呼吸障碍的发展是肥胖，男性性别， 年龄增长。上呼吸道阻塞的确切机制， 睡眠中的低通气是未知的。目前，据信， 事件是由于机械因素或神经肌肉控制的改变 是由肥胖引起的我们的总体假设是， 与反射机制的进行性缺陷相关， 睡眠中的气道阻塞和换气不足。而且我们有证据 减肥可以改善睡眠呼吸紊乱，我们现在希望 确定这种改善是否是由于反射控制的恢复 机制，并确定神经体液机制， 综合征的小鼠模型。在一系列的横截面和纵向 实验中，我们将研究肥胖对上呼吸道的影响， 排泄功能及其通过体重减轻的调节。在具体目标1中， 假设上气道压力-流量关系中的反应， 舌下神经的电刺激更有效（a）当 塌陷部位在口咽区域，（B）在患有 降低体重指数。在具体目标2中，我们假设 对鼻压和CO2的反射反应存在于（a） 阻塞性睡眠呼吸暂停与正常对照，以及（B）该缺陷取决于 肥胖的程度。在具体目标3中，我们假设减肥 会恢复对鼻压和二氧化碳的反射反应在具体目标4中，我们 假设（a）随着体重减轻， 需要完整的瘦素轴，和（B）瘦素的保护作用是 在女性和男性中增强。该提案发展并利用了 特别是量化的机械和神经肌肉的基础， 人类上呼吸道神经肌肉控制障碍（特定目的 1-3）。提出了在鼠模型中的补充实验，以 探索神经体液机制负责的变化， 控制（具体目标4）。拟议的研究旨在阐明 探讨睡眠障碍的病理生理基础，探索新的治疗方法 呼吸了

DESCRIPTION (Applicant's abstract): Sleep disordered breathing is characterized by upper airway obstruction and hypoventilation during sleep. Obstructive sleep apnea is the most common form of sleep disordered breathing, and is due to recurrent collapse of the upper airway during sleep. The major risk factors for the development of sleep disordered breathing are obesity, male gender, and increasing age. The precise mechanism for upper airway obstruction and hypoventilation during sleep are unknown. Currently, it is believed that these events are due to alterations in mechanical factors or neuromuscular control precipitated by obesity. It is our overall hypothesis that obesity is associated with progressive defects in reflex mechanisms that lead to upper airway obstruction and hypoventilation during sleep. Moreover, we have evidence that weight loss ameliorates sleep disordered breathing, and we now wish to determine whether this improvement is due to restoration of reflex control mechanisms in the human and to determine the neurohumoral mechanisms in a murine model of the syndrome. In a series of cross sectional and longitudinal experiments, we will examine the effects of obesity on upper airway and ventilatory function, and its modulation by weight loss. In Specific Aim 1, we hypothesize that the response in upper airway pressure-flow relationships to electrical stimulation of the hypoglossal nerve is more effective (a) when the locus of collapse is in the oropharyngeal region and (b) in patients with a lower body mass index. In Specific Aim 2, we hypothesize that a defect in reflex responses to nasal pressure and CO2 exists in (a) patients with obstructive sleep apnea vs. normal controls, and (b) that this defect depends upon the degree of obesity. In Specific Aim 3, we hypothesize that weight loss will restore reflex responses to nasal pressure and CO2. In Specific Aim 4, we hypothesize that (a) changes in neuroventilatory control with weight loss requires an intact leptin axis, and (b) the protective effect of leptin is enhanced in females vs. males. This proposal develops and utilizes methods specifically to quantitate the mechanical and neuromuscular basis for disturbances in upper airway neuromuscular control in humans (Specific Aims 1-3). Complementary experiments in a murine model are proposed in order to probe neurohumoral mechanisms responsible for alterations in ventilatory control (Specific Aim 4). The proposed studies are designed to elucidate the pathophysiologic basis and to explore novel treatments for sleep disordered breathing.