Elucidating Inflammatory and Metabolic Pathways in Obstructive Sleep Apnea Development

阐明阻塞性睡眠呼吸暂停发展中的炎症和代谢途径

• 批准号: 10227002
• 负责人: Tianyi Huang
• 金额: $ 17.71万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-20 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227002
• 关键词: Address; Adipose tissue; Adult; Age; Anti-Inflammatory Agents; Apnea; Archives; Area; Attenuated; Biological; Biological Assay; Biological Markers; Biometry; Blood; Blood specimen; Body fat; Body mass index; C-reactive protein; Cardiovascular Diseases; Central obesity; Cholesterol; Chronic; Collection; Complement; Consult; Cross-Sectional Studies; Data; Data Collection; Development; Device Designs; Devices; Diabetes Mellitus; Diagnosis; Diagnostic; Diet; Dimensions; Disease; Drowsiness; Epidemiology; Etiology; FDA approved; Fatty acid glycerol esters; Follow-Up Studies; Foundations; Future; Genes; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genetic Risk; Goals; Health; Health Professional; Heterogeneity; High Density Lipoprotein Cholesterol; High Prevalence; Home; Incidence; Inflammation; Inflammatory; Insulin; Interleukin-6; Intervention; Lead; Leptin; Life Style; Link; Low-Density Lipoproteins; Measures; Mechanics; Mediating; Mendelian randomization; Mentors; Metabolic; Metabolic Pathway; Metabolic dysfunction; Metabolic syndrome; Methods; Multi-Ethnic Study of Atherosclerosis; Nurses' Health Study; Obesity; Observational Study; Obstructive Sleep Apnea; Oxygen; Participant; Pathogenesis; Pathogenicity; Pathway interactions; Patient Self-Report; Pharmacologic Substance; Physiology; Polysomnography; Population; Prevention; Prevention strategy; Prospective Studies; Prospective cohort; Reporting; Research; Research Personnel; Risk; Risk Factors; Role; Sample Size; Sampling; Sex Differences; Single Nucleotide Polymorphism; Sleep; Sleep Apnea Syndromes; Sleep Disorders; Sum; TNF gene; Therapeutic; Training; Waist-Hip Ratio; Woman; Work; active lifestyle; airway muscle; base; cardiovascular disorder risk; circulating biomarkers; cohort; comorbidity; design; epidemiology study; evidence base; follow-up; gene environment interaction; genetic analysis; genetic association; genetic variant; high risk; high risk population; hypercholesterolemia; improved; indexing; innovation; insight; instrument; lean body mass; men; metabolomics; mortality; non-genetic; novel; population based; portability; predictive marker; prospective; pulmonary function; screening; sex; skills; therapeutic target

ABSTRACT Obstructive sleep apnea (OSA) is a common chronic sleep disorder in adults with a serious impact on health. In addition to age and sex, obesity has been identified as the strongest risk factor for OSA. However, the underlying mechanisms linking obesity with OSA pathogenesis are not fully understood. Although accumulating evidence (based predominantly on cross-sectional studies) suggests that inflammation and metabolic dysfunction may represent two potential modifiable etiologic pathways for OSA, few population- based, prospective studies have been conducted to evaluate their roles in OSA development. In this highly translational project, I will leverage the wealth of data from 4 large prospective US cohorts: the Nurses' Health Study (NHS), NHSII, the Health Professional Follow-up Study (HPFS) and the Multi-Ethnic Study of Atherosclerosis (MESA). I will use genetic and biomarker-based approaches to elucidate the importance of inflammatory and metabolic pathways in OSA etiology. In Aim 1, I will use Mendelian randomization to examine whether genetic susceptibility to obesity, inflammation and metabolic dysfunction is associated with higher risk of developing OSA. Results from Mendelian randomization will help distinguish causal from non- causal associations that arise from non-genetic, cross-sectional, observational studies due to confounding or reverse causation. I will further examine gene-lifestyle interactions and sex differences in these genetic associations. In Aim 2, I will evaluate whether inflammatory (e.g., CRP, IL-6, TNF-α) and metabolic (e.g., metabolomics, insulin, leptin, cholesterol) biomarkers that have been measured from archived blood samples predict sleep-disordered breathing. These biomarkers will provide further insights into the mechanistic pathways that may serve as potential therapeutic and pharmaceutical targets for intervention. Lastly, I will measure sleep-disordered breathing in 200 NHS/NHSII/HPFS participants using an FDA-approved device designed for at-home OSA diagnosis, and replicate the biomarker associations in Aim 2 with the objective measures. I will acquire additional expertise in sleep epidemiology, OSA physiology, genetic analysis, and primary sleep data collection/management. My training and research will be guided by a world-class mentoring/consulting team, each with substantial expertise in the core areas: Drs. Susan Redline (OSA), Frank Hu (lifestyles), Shelley Tworoger (biomarkers), Richa Saxena (genetics), Clary Clish (metabolomics) and Eric Tchetgen Tchetgen (biostatistics). In sum, this innovative project will advance our understanding of the inflammatory and metabolic pathways in OSA development from multiple dimensions, and help me emerge as an independent investigator with unique interdisciplinary skills in sleep/OSA epidemiology research.

摘要 阻塞性睡眠呼吸暂停（OSA）是一种常见的慢性睡眠障碍，严重影响成人的健康。 除了年龄和性别之外，肥胖已被确定为OSA的最大风险因素。但 将肥胖与OSA发病机制联系起来的潜在机制尚未完全了解。虽然 越来越多的证据（主要基于横断面研究）表明，炎症和 代谢功能障碍可能代表OSA的两种潜在的可改变的病因学途径，少数人群- 的基础上，前瞻性研究已经进行了评估他们的作用，在OSA的发展。在这个高度 作为一个翻译项目，我将利用来自4个大型前瞻性美国队列的丰富数据： 研究（NHS），NHSII，卫生专业人员随访研究（HPFS）和多种族研究 动脉粥样硬化（梅萨）。我将使用遗传学和生物标志物为基础的方法来阐明的重要性， 炎症和代谢途径在OSA病因学中的作用。在目标1中，我将使用孟德尔随机化， 检查肥胖、炎症和代谢功能障碍的遗传易感性是否与 患OSA的风险更高。孟德尔随机化的结果将有助于区分因果关系和非因果关系。 由于混杂因素，非遗传性、横断面、观察性研究产生的因果关系，或 反向因果关系我将进一步研究基因-生活方式的相互作用和性别差异在这些遗传 协会.在目标2中，我将评估是否有炎症（例如，CRP、IL-6、TNF-α）和代谢（例如， 代谢组学、胰岛素、瘦素、胆固醇）生物标志物 预测睡眠呼吸紊乱这些生物标志物将提供进一步的了解机制， 可能作为潜在的治疗和药物干预目标的途径。最后，我将 使用FDA批准的设备测量200名NHS/NHSII/HPFS参与者的睡眠呼吸障碍 设计用于家庭OSA诊断，并复制目标2中的生物标志物关联， 措施我将获得睡眠流行病学，OSA生理学，遗传分析， 主要睡眠数据收集/管理。我的训练和研究将由世界级的 指导/咨询团队，每个人都在核心领域拥有丰富的专业知识：Susan Redline博士（OSA），Frank Hu（生活方式），Shelley Tworoger（生物标志物），Richa Saxena（遗传学），Clary Clish（代谢组学）和Eric Tchetgen Tchetgen（生物统计学）。总之，这个创新的项目将促进我们对 炎症和代谢途径在OSA的发展从多个层面，并帮助我出现， 在睡眠/OSA流行病学研究方面具有独特跨学科技能的独立调查员。