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: 8526495
• 负责人: Allan I Pack
• 金额: $ 226.36万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8526495
• 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.

该计划项目拨款 (PPG) 重点关注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 OSA 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。由于肥胖也被认为会产生相同的影响，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非常重要。该研究计划有三个项目和五个核心。项目 01（PL，R. Schwab 博士）针对肥胖为何导致 OSA 的问题。提出其主要发病机制是舌头和其他上气道结构的脂肪浸润，导致其尺寸增大，从而缩小气道尺寸并影响肌肉功能。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以及肥胖大鼠模型中得到解决。该项目将使用新颖、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. Kuna 博士）中，组建了一个多学科团队来解决肥胖是否会削弱 OSA 治疗对胰岛素抵抗、高血压和心血管功能的益处，因为在没有 OSA 的情况下肥胖会产生这些益处。影响。该研究旨在分别评估内脏脂肪含量较低和较高的个体的治疗效果。该研究还评估了相关过程的生物标志物的变化——氧化、交感神经活性、促炎细胞因子、粘附分子和游离脂肪酸。纳入不含 OSA 的对照，以评估 OSA 是否导致临床终点发生不可逆转的变化。项目 03（PL，A. Pack 博士）建议评估 OSA 受试者在使用 CPAP 有效治疗之前和之后睡眠期间生物标志物的时间变化。推动该项目的理念是，研究睡眠期间这些过程的变化提供了 OSA 的分子特征。研究针对患有 OSA（伴有或不伴有心血管后果）的肥胖和瘦弱个体以及对照组进行。有人认为，肥胖会改变 OSA 生物标志物反应的性质，患有 OSA 且患有合并症的人比没有患有合并症的人具有更大的氧化应激和炎症状态。 PPG 由五个核心支持（A：管理；B：睡眠研究和招募；C：成像；D：生物标记；E：生物统计和数据管理）。因此，该 PPG 专注于一个常见的临床问题。该计划将确定哪些 OSA 患者可以从治疗中受益以及不同终点的获益程度。它将带来 OSA 的新分子特征，从而以一种新的、具有成本效益的方式改变该领域的医学实践。