OBESITY AND NEURAL CONTROL IN SLEEP DISORDERED BREATHING

肥胖与睡眠呼吸障碍的神经控制

• 批准号: 6526698
• 负责人: PHILIP L SMITH
• 金额: $ 43.56万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-01-20 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6526698
• 关键词: carbon dioxide; clinical research; disease /disorder model; electrostimulus; gender difference; human subject; hypoglossal nerve; hypoventilation; laboratory mouse; leptin; longitudinal human study; neuromuscular function; neuroregulation; obesity; pharynxs; respiration regulatory center; respiratory airflow disorder; respiratory airflow measurement; respiratory airway pressure; respiratory airway volume; respiratory muscles; respiratory reflex; sleep apnea; weight loss

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.

描述（申请人的摘要）：呼吸的睡眠失调 在睡眠期间通过上呼吸道阻塞和不足衰减。阻塞性睡眠 呼吸暂停是睡眠失调呼吸的最常见形式，是由于 睡眠期间上呼吸道的复发性崩溃。主要风险因素 睡眠无序呼吸的发展是肥胖，男性性别和 年龄增加。上呼吸道阻塞的确切机制和 睡眠期间的不足剂量尚不清楚。目前，人们相信这些 事件是由于机械因子或神经肌肉控制的改变造成的 肥胖沉淀。我们的总体假设是肥胖是 与反射机制的进行性缺陷相关的导致上部 气道障碍物和睡眠期间的衰减不足。而且，我们有证据 减肥可以改善睡眠失调的呼吸，我们现在希望 确定这种改进是否是由于反射控制的恢复 人类的机制并确定A中的神经肿瘤机制 综合征的鼠模型。在一系列横截面和纵向中 实验，我们将检查肥胖对上呼吸道的影响 通气功能及其通过体重减轻的调节。在特定目标1中，我们 假设上空气道压力流的响应对 降压神经的电刺激更有效（a） 塌陷的基因座位于口咽区域，（b）在患有A的患者中 下体重指数。在特定目标2中，我们假设一个缺陷 （a）患者存在对鼻压和二氧化碳的反射反应 阻塞性睡眠呼吸暂停与正常对照，（b）此缺陷取决于 根据肥胖程度。在特定目标3中，我们假设体重减轻 将恢复对鼻压和二氧化碳的反射反应。在特定的目标4中，我们 假设（a）随着体重减轻而改变神经源性控制 需要完整的瘦素轴，（b）瘦素的保护作用 女性与男性的增强。该建议开发并利用方法 专门用于定量机械和神经肌肉的基础 人类上部气道神经肌肉控制的扰动（特定目的 1-3）。提出了鼠模型中的互补实验，以便 负责通气改变的探针神经肿瘤机制 控制（特定目标4）。拟议的研究旨在阐明 病理生理基础并探索睡眠失调的新型治疗方法 呼吸。