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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

抽象的阻塞性睡眠呼吸暂停（OSA）是成人常见的慢性睡眠障碍，严重影响健康。除年龄和性别外，肥胖已被确定为 OSA 的最强危险因素。肥胖与 OSA 发病机制之间的联系尚不完全清楚。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病因学途径，少数人群在此基础上，进行了前瞻性研究来评估它们在 OSA 发展中的作用。在转化项目中，我将利用来自美国 4 个大型前瞻性队列的丰富数据：护士健康研究 (NHS)、NHSII、健康专业随访研究 (HPFS) 和多种族研究我将使用基于遗传和生物标记的方法来阐明动脉粥样硬化（MESA）的重要性。在目标 1 中，我将使用孟德尔随机化来研究 OSA 病因学中的炎症和代谢途径。检查对肥胖、炎症和代谢功能障碍的遗传易感性是否与孟德尔随机化的结果将有助于区分因果因素和非因素。由于混杂或非遗传、横断面、观察性研究而产生的因果关系我将进一步研究基因与生活方式的相互作用以及这些遗传中的性别差异。在目标 2 中，我将评估炎症（例如 CRP、IL-6、TNF-α）和代谢（例如从存档的血液样本中测量的代谢组学、胰岛素、瘦素、胆固醇）生物标志物这些生物标志物将提供对睡眠呼吸障碍的机制的进一步见解。最后，我将探讨可能作为干预的潜在治疗和药物靶点的途径。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专为家庭 OSA 诊断而设计，并复制目标 2 中的生物标志物关联，以实现目标我将获得睡眠流行病学、OSA 生理学、遗传分析和睡眠流行病学方面的更多专业知识。我的主要睡眠数据收集/管理将由世界一流的指导。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 (OSA) 博士、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 总之，这个创新项目将增进我们对生物统计学的理解。从多个维度了解 OSA 发展中的炎症和代谢途径，并帮助我成为在睡眠/OSA 流行病学研究方面具有独特跨学科技能的独立调查员。