Endophenotypes of Sleep Apnea and Role of Obesity

该计划项目资助（PPG）的重点是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的主要危险因素。OSA患者存在与肥胖无关的氧化应激、交感神经激活和炎症状态增加。由于肥胖也被假定产生相同的影响，并且OSA和肥胖通常共存，因此考虑这两种发病过程的相对作用是很重要的。研究计划有三个项目和五个核心。01项目（PL, Dr. R. Schwab）针对的问题是为什么肥胖会导致阻塞性睡眠呼吸暂停。提出其主要发病机制为脂肪浸润舌部及其他上气道结构，使其体积增大，从而使气道体积减小，影响肌肉功能。这将在人类病例对照研究、减肥手术后减肥个体的纵向研究和肥胖大鼠模型中得到解决。该项目将使用最新的核磁共振成像技术来评估舌头和其他结构中的脂肪。在Project 02 （PL， S. Kuna博士）中，一个多学科团队已经成立，研究肥胖是否会减弱OSA治疗对胰岛素抵抗、高血压和心血管功能的益处，因为没有OSA的肥胖会产生这些影响。该研究旨在分别评估低脂肪和高脂肪个体的治疗效果。该研究还评估了相关过程中生物标志物的变化——氧化、交感神经活动、促炎细胞因子、粘附分子和游离脂肪酸。纳入无OSA的对照组，以评估OSA是否会导致临床终点的不可逆变化。Project 03 （PL, Dr. A. Pack）建议评估OSA患者在CPAP有效治疗前后睡眠期间生物标志物的时间变化。激发这个项目的概念是，研究睡眠期间这些过程的变化提供了OSA的分子特征。研究对象是患有阻塞性睡眠呼吸暂停的肥胖和瘦弱个体，有或没有心血管后果，以及对照组。肥胖会改变对OSA的生物标志物反应的性质，并且患有OSA合并症的个体会比那些没有合并症的个体有更大的氧化应激和炎症状态。PPG由五个核心（A：行政管理；B：睡眠研究和招募；C：成像；D：生物标志物；E：生物统计和数据管理）提供支持。因此，本PPG的重点是一个常见的临床问题。该项目将确定哪些OSA患者从治疗中获益，以及不同终点的获益程度。这将导致一种新的OSA分子特征，可以以一种新的，具有成本效益的方式改变该领域的医学实践。

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.