Mechanisms and Consequences of Intermittent Hypoxia-Induced Lipolysis

应聘者：Jonathan Jun博士最近在约翰霍普金斯大学完成了一项为期5年的肺部、重症监护和睡眠医学研究。他一直在Vsevolod Polotsky博士的实验室工作，他是在小鼠身上使用间歇性低氧(IH)来研究阻塞性睡眠呼吸暂停(OSA)的代谢后果的先驱。在这项提案中，Jun博士测试了一种新的理论来解释IH引起的代谢功能障碍。环境：Jun博士是肺/重症监护医学部的讲师，从2011年7月1日开始从事临床医生和科学家的职业生涯。他将通过波洛茨基博士以及约翰·霍普金斯大学和马里兰大学的生理学和新陈代谢专家小组，接受持续的培训和支持。研究：OSA是一种常见的疾病，其特征是反复上呼吸道塌陷，导致IH和睡眠碎片。阻塞性睡眠呼吸暂停综合征可能导致代谢功能障碍和动脉粥样硬化性心血管疾病，从而导致西方世界死亡和残疾的主要原因。一些研究人员已经证明实验性高血压会导致胰岛素抵抗和高脂血症。然而，这些由高血压引起的代谢异常的基础尚不清楚。我们推测，在IH期间，游离脂肪酸(FFA)的升高可能导致代谢功能障碍。游离脂肪酸是脂肪组织在脂肪分解过程中释放的循环脂质，过量时会导致胰岛素抵抗、脂肪肝和高脂血症。我们最近报道，OSA在睡眠中会迅速增加血浆FFA，而补充氧气可以消除这种作用。这一观察启发了这一建议的核心假设，即(1)IH期间的脂解是通过对交感神经系统的颈动脉体部刺激而发生的，以及(2)慢性IH诱导的脂解促进组织脂质堆积，导致胰岛素抵抗和血脂异常。模拟阻塞性睡眠呼吸暂停综合征患者经历的氧气减饱和的IH小鼠模型已经被开发出来验证这些假说。在IH期间，小鼠的FFA和甘油水平迅速升高。在特定的目标1中，我们将利用缺乏正常颈动脉体功能的小鼠，确定颈动脉小体在IH期间刺激脂解的作用。具体目标2将通过使用β受体阻滞剂，确定交感神经系统在刺激IH期间脂肪分解中的作用。具体目标3将确定是否可以通过抑制脂解来预防慢性IH后的胰岛素抵抗和高脂血症。

DESCRIPTION (provided by applicant): Mechanisms and Consequences of Intermittent Hypoxia-Induced Lipolysis Candidate: Dr. Jonathan Jun recently completed a 5-year fellowship at Johns Hopkins in Pulmonary, Critical Care, and Sleep Medicine. He has been working in the laboratory of Dr. Vsevolod Polotsky, a pioneer in the use of intermittent hypoxia (IH) in mice to study metabolic consequences of obstructive sleep apnea (OSA). In this proposal, Dr. Jun tests a novel theory to explain the metabolic dysfunction induced by IH. Environment: Dr. Jun is an Instructor in the Division of Pulmonary/Critical Care Medicine beginning on July 1, 2011 to pursue a clinician-scientist career. He will receive ongoing training and support through Dr. Polotsky and a panel of experts in physiology and metabolism at Johns Hopkins and the University of Maryland. Research: OSA is a common condition characterized by repetitive upper airway collapse, causing IH and sleep fragmentation. OSA may predispose to metabolic dysfunction and atherosclerotic cardiovascular disease, thereby contributing to the leading causes of death and disability in the Western world. Several investigators have demonstrated that experimental IH causes insulin resistance and hyperlipidemia. However the basis for these IH-induced metabolic abnormalities is not understood. We hypothesize that elevations of free fatty acids (FFA) may cause metabolic dysfunction during IH. FFA are circulating lipids released by adipose tissue during lipolysis, which in excess induce insulin resistance, fatty liver, and hyperlipidemia. We recently reported that OSA rapidly increases plasma FFA during sleep, which is abolished by supplemental oxygen. This observation inspired the hypotheses central to this proposal, that (1) lipolysis during IH occurs through carotid body stimulation of the sympathetic nervous system, and that (2) chronic IH-induced lipolysis promotes tissue lipid accumulations leading to insulin resistance and dyslipidemia. A mouse model of IH, simulating oxygen desaturations experienced by patients with OSA, has been developed to test these hypotheses. Mice exhibit rapid increases in FFA and glycerol levels during IH. In Specific Aim 1, we will establish the role of the carotid body in stimulating lipolysis during IH, using mice lackig normal carotid body function. Specific Aim 2 will establish the role of the sympathetic nervous system in stimulating lipolysis during IH, using beta blockade. Specific Aim 3 will establish whether insulin resistance and hyperlipidemia following chronic IH can be prevented with the suppression of lipolysis.