Endophenotypes of Sleep Apnea and Role of Obesity

该计划项目拨款(PPG)专注于阻塞性睡眠呼吸暂停(OSA)的常见问题及其与肥胖的关系。OSA患者不仅会出现过度嗜睡，而且患高血压、胰岛素抵抗和心血管事件的风险也会增加。肥胖是阻塞性睡眠呼吸暂停综合征的主要危险因素。OSA患者有氧化应激、交感神经激活和炎症状态增加，这些与肥胖无关。由于肥胖也被认为会产生相同的影响，而且OSA和肥胖普遍共存，因此考虑这两个致病过程的相对作用是很重要的。该研究计划有三个项目和五个核心。项目01(PL，R.Schwab博士)针对的是为什么肥胖导致阻塞性睡眠呼吸暂停的问题。认为其主要发病机制是舌及其他上呼吸道结构的脂肪渗入，使其体积增大，从而使气道变小，影响肌肉功能。这将在一项人类病例对照研究、一项关于减肥手术后体重减轻的长期研究以及肥胖大鼠模型中得到解决。该项目将使用新的、最先进的核磁共振技术来评估舌头和其他结构中的脂肪。在项目02(PL，S·库纳博士)中，已经组建了一个多学科团队来研究肥胖的存在是否会削弱OSA治疗对胰岛素抵抗、高血压和心血管功能的好处，因为没有OSA的肥胖会产生这些影响。这项研究的目的是分别评估内脏脂肪含量较高和较低的个体的治疗效果。该研究还评估了相关过程的生物标记物的变化--氧化、交感活性、炎性细胞因子、黏附分子和游离脂肪酸。纳入没有OSA的对照，以评估OSA是否导致临床终点的不可逆转变化。项目03(PL，Dr.A.Pack)建议评估阻塞性睡眠呼吸暂停患者在CPAP有效治疗前后睡眠中生物标志物的时间变化。推动这个项目的概念是，研究睡眠期间这些过程的变化提供了阻塞性睡眠呼吸暂停综合征的分子特征。研究对象为肥胖和消瘦的阻塞性睡眠呼吸暂停患者，分别有无心血管后果和对照组。有人认为，肥胖会改变OSA生物标记物的反应性质，与没有OSA的人相比，患有OSA并存的人将有更大的氧化应激和炎症状态。PPG由五个核心支持(A：行政；B：睡眠研究和招募：C：成像；D：生物标记物；以及E：生物统计和数据管理)。因此，这个PPG集中在一个常见的临床问题上。该计划将确定谁患有阻塞性睡眠呼吸暂停综合症从治疗中受益，以及不同终点的受益程度。它将导致OSA的新分子签名，可能以一种新的、具有成本效益的方式改变这一领域的医学实践。

This Program Project Grant (PPG) is focused on the common problem of obstructive sleep apnea (OSA) and its relationship with obesity. Patients with OSA not only develop excessive sleepiness, but are at increased risk for hypertension, insulin resistance and cardiovascular events. Obesity is the major risk factor for OSA. Patients with OSA have oxidative stress, sympathetic activation, and increased inflammatory state that are independent of obesity. Since obesity is also postulated to produce identical effects, and OSA and obesity common coexist, it is important to consider the relative role of these two pathogenetic processes. The program of research has three projects and five cores. Project 01 (PL, Dr. R. Schwab) is directed at the question as to why obesity leads to OSA. It is proposed that the major pathogenetic mechanism is fat infiltration of tongue and other upper airway structures that increase their size, thereby reducing airway size and affecting the function of muscle. This will be addressed in a human case-control study, in a longidutinal study of individuals loosing weight after bariatric surgery, and in rat models of obesity. The project will use novel, state-of-the-art MRI techniques to assess fat in tongue and other structures. In Project 02 (PL, Dr. S. Kuna), a multidisciplinary team has been assembled to address whether the presence of obesity attenuates benefits of treatment of OSA on insulin resistance, hypertension and CV function, since obesity in the absence of OSA produces these effects. The study is powered to separately assess treatment effects in individuals with low and higher amounts of visceral fat. The study also assesses changes in biomarkers of the relevant processes-oxidation, sympathetic activity, proflammatory cytokines, adhesion molecules and free fatty acids. Controls without OSA are included to assess whether OSA leads to irreversible changes in clinical end-points. Project 03 (PL, Dr. A. Pack) proposes to assess temporal changes in biomarkers during sleep in subjects with OSA both before and after effective treatment with CPAP. The concept that movitates this project is that studying change in these processes across the sleep period provides a molecular signature of OSA. Studies are done in obese and lean individuals with OSA with and without cardiovascular consequences and in controls. It is argued that obesity will alterthe nature of the biomarker response to OSA, and individuals with OSA who develop comorbidities will have greater oxidative stress and inflammatory state than those who do not. The PPG is supported by five cores (A: Administrative; B: Sleep Study and Recruitment: C: Imaging; D: Biomarker; and E: Biostatistical and Data Management). Thus, this PPG is focused on a common clinical problem. The program will lead to defining who with OSA benefits from therapy and the magnitude of benefit for different end-points. It will lead to a new molecular signature of OSA that could transform the practice of medicine in this area in a new, cost-effective way.