Endophenotypes of Sleep Apnea and Role of Obesity

睡眠呼吸暂停的内表型和肥胖的作用

• 批准号: 8478277
• 负责人: Allan I Pack
• 金额: $ 8.01万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8478277
• 关键词: Address; Affect; Animals; Apnea; Area; Attenuated; Biological Markers; Breathing; Cardiovascular Diseases; Cardiovascular system; Case-Control Studies; Cell Adhesion Molecules; Clinical; Clinical and Translational Science Awards; Comorbidity; Continuous Positive Airway Pressure; Country; Diabetes Mellitus; Disease; Epidemic; Epidemiologic Studies; Event; Excessive Daytime Sleepiness; Fatty acid glycerol esters; Female; Free Radicals; Health; Human; Hypertension; Image; Incidence; Individual; Infiltration; Inflammatory; Insulin Resistance; Intervention Studies; Lead; Link; Literature; Magnetic Resonance Imaging; Measurement; Mediating; Medicine; Meta-Analysis; Modeling; Molecular; Molecular Profiling; Muscle function; Nature; Nonesterified Fatty Acids; Obesity; Obstructive Sleep Apnea; Oxidative Stress; Oxygen; Pathway interactions; Patients; Pattern; Prevalence; Process; Production; Program Research Project Grants; Public Health; Publishing; Rattus; Relative (related person); Research; Risk; Risk Factors; Role; Sleep; Sleep Apnea Syndromes; Structure; Techniques; Time; Tongue; United States; Visceral; Weight; adverse outcome; bariatric surgery; base; cost effective; cytokine; data management; design; effective therapy; endophenotype; human subject; hypercholesterolemia; male; medical schools; member; middle age; multidisciplinary; novel; oxidation; pandemic disease; programs; response; treatment effect

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.

该计划项目赠款（PPG）的重点是阻塞性睡眠呼吸暂停（OSA）及其与肥胖的关系。 OSA患者不仅会出现过度的嗜睡，而且有高血压，胰岛素抵抗和心血管事件的风险增加。肥胖是OSA的主要危险因素。 OSA患者具有氧化应激，交感神经激活以及与肥胖无关的炎症状态增加。由于肥胖症也被假定会产生相同的效果，并且OSA和肥胖共存共存，因此重要的是要考虑这两个致病过程的相对作用。研究计划有三个项目和五个核心。项目01（PL，R。Schwab博士）针对了为什么肥胖导致OSA的问题。有人提出，主要的致病机制是舌头的脂肪浸润和其他上呼吸道结构增加了大小，从而降低了气道的大小并影响肌肉的功能。这将在人类病例对照研究，在减肥手术后失去体重的个体以及肥胖大鼠模型的长期研究中解决。该项目将使用新颖的，最先进的MRI技术来评估舌头和其他结构的脂肪。在项目02（PL，S。Kuna博士）中，已经组装了一个多学科团队，以解决肥胖的存在是否会减弱OSA治疗对胰岛素抵抗，高血压和CV功能的益处，因为在没有OSA的情况下肥胖会产生这些影响。该研究有动力分别评估低和更高内脏脂肪的个体的治疗效果。该研究还评估了相关过程氧化，交感活性，大量细胞因子，粘附分子和游离脂肪酸的生物标志物的变化。包括没有OSA的控件来评估OSA是否导致临床终点的不可逆转变化。项目03（PL，A。Pack博士）提议评估在有效治疗CPAP之前和之后，在患有OSA的受试者中睡眠期间生物标志物的时间变化。动作该项目的概念是在整个睡眠期间研究这些过程的变化提供了OSA的分子签名。研究是在具有和没有心血管后果的OSA肥胖和瘦肉中进行的。有人认为，肥胖症将改变生物标志物对OSA的反应的本质，而患有OSA的人会比没有的氧化应激和炎症状态更大。 PPG得到五个核心的支持（A：行政； B：睡眠研究和招聘：C：Imaging； D：生物标志物； E：Biostatistic和数据管理）。因此，该PPG专注于常见的临床问题。该计划将导致定义谁能从疗法中受益的OSA受益以及不同终点的收益幅度。它将导致OSA的新分子签名，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。