LEPTIN AND VENTILATORY CONTROL DURING SLEEP

肥胖症的患病率在西方社会急剧增加，特别是在美国，其中22%的人口的体重指数大于30 kg/m2。随着体重的增加，个体可发展出PaCO 2的静息水平升高和高碳酸血症性反应降低（肥胖低通气综合征; OHS）。肥胖和呼吸抑制之间的联系机制尚不清楚。这一提议的前提是，最近克隆的代谢激素--瘦素--可以预防肥胖时的呼吸抑制。我们的研究结果表明，肥胖的ob/ob小鼠，缺乏循环瘦素，表现出OHS的主要临床特征，瘦素替代逆转呼吸抑制独立的重量。本研究旨在探讨瘦素对大鼠大脑皮层运动控制的影响，以及调节瘦素作用的途径和因素。采用各种转基因小鼠和新技术来测量慢性仪器小鼠的通气量、睡眠/觉醒/状态和动脉血气。从小鼠实验中获得的见解将应用于人类，以定义瘦素与肥胖通气之间的关系。具体目标1，检查瘦素是否可以增加中枢化学感受器的增益，以及肥胖小鼠体内脂肪急性减少10%是否影响排泄控制。具体目标2检查瘦素是否通过下丘脑和外周化学感受器通路来改变呼吸控制。具体目标3，检查瘦素是否上调作为慢性缺氧的代偿反应。在具体目标4中，将扩展机制动物研究，以确定CNS中的瘦素水平如何与严重肥胖人群的PaCO 2相关。最后，将在具体目标1-4中探讨性别和睡眠/清醒状态的作用。这些研究将提高对肥胖呼吸衰竭发病机制的认识，为了解瘦素在其他原因引起的呼吸衰竭患者中的作用提供线索，并提供特异性治疗干预的可能性。

The prevalence of obesity is increasing dramatically in western society, especially in the U.S. where 22% of the population have a body mass index greater than 30 kg/m2. As weight is gained, individuals can develop elevated, resting levels of PaCO2 and depressed hypercapnic ventilatory responses (Obesity Hypoventilation Syndrome; OHS). The mechanisms that link obesity and respiratory depression are unclear. The premise of this proposal is that the recently cloned metabolic hormone, leptin, can prevent respiratory depression in obesity. Our findings indicate that obese ob/ob mice, which lack circulating leptin, exhibit the major clinical features of OHS, and that leptin replacement reverses respiratory depression independent of weight. The current application is designed to explore influences of leptin on ventilatory control, and the pathways and factors which modulate its effect. Various transgenic mice and novel techniques are employed to measure ventilation, sleep wake/state and arterial blood gases in chronically instrumented mice. Insights gained from murine experiments will be applied in humans to define the relationship between leptin and ventilation in obesity. Specific Aim l, examines whether leptin can increase the gain of central chemoreceptors, and whether an acute 10% reduction in body fat in obese mice affects ventilatory control. Specific Aim 2 examines whether leptin acts through hypothalamic and peripheral chemoreceptor pathways to alter respiratory control. Specific Aim 3, examines whether leptin is upregulated as a compensatory response to chronic hypoxia. In Specific Aim 4, the mechanistic animal studies will be extended to determine how leptin levels in the CNS relate to PaCO2 in severely obese humans. Finally, the role of gender and sleep/wake state will be explored across Specific Aims 1-4. These studies will enhance understanding of the pathogenesis of respiratory failure in obesity, provide insight into the role of leptin in patients with ventilatory insufficiency of other causes, and offer the possibility of specific therapeutic intervention.