Metabolomics of obstructive sleep apnea

阻塞性睡眠呼吸暂停的代谢组学

基本信息

批准号：
10204094
负责人：
Aalim M Weljie
金额：
$ 111.99万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10204094
关键词：
Address Apnea Arousal Atrial Fibrillation Automobile Driving Biological Markers Blood Body Weight decreased Cardiometabolic Disease Characteristics Clinic Clinical Collaborations Continuous Positive Airway Pressure Data Data Collection Dementia Diabetes Mellitus Disease Drowsiness European Union Fingerprint Frequencies Functional disorder Funding Future Glycosylated hemoglobin A Heart Diseases Heterogeneity Hour Hypertension Hypoxia Individual Insulin Resistance Link Malignant Neoplasms Measures Metabolic Metabolism Methods Molecular Monitor National Heart, Lung, and Blood Institute Nerve Degeneration Obesity Observational Study Obstructive Sleep Apnea Occupations Pathway interactions Patients Periodicity Phenotype Prevalence Prospective Studies Proteomics Protocols documentation Publications Randomized Recurrence Research Research Project Grants Risk Risk Factors Role Safety Sampling Severities Site Sleep Sleep Apnea Syndromes Sleep Disorders Sleep Fragmentations Sleep disturbances Sleeplessness Societies Stroke Symptoms Techniques Treatment Efficacy United States National Institutes of Health base cardiovascular risk factor case control causal model clinical application clinical care clinical phenotype clinical practice clinical subtypes design disease heterogeneity disorder subtype epigenomics improved indexing individual patient insight metabolic abnormality assessment metabolomics mortality non-alcoholic fatty liver disease novel patient population patient subsets personalized diagnostics personalized medicine precision medicine pressure prognostic prospective response sample collection sleep regulation treatment response weight loss intervention

Address Apnea Arousal Atrial Fibrillation Automobile Driving Biological Markers Blood Body Weight decreased Cardiometabolic Disease Characteristics Clinic Clinical Collaborations Continuous Positive Airway Pressure Data Data Collection Dementia Diabetes Mellitus Disease Drowsiness European Union Fingerprint Frequencies Functional disorder Funding Future Glycosylated hemoglobin A Heart Diseases Heterogeneity Hour Hypertension Hypoxia Individual Insulin Resistance Link Malignant Neoplasms Measures Metabolic Metabolism Methods Molecular Monitor National Heart, Lung, and Blood Institute Nerve Degeneration Obesity Observational Study Obstructive Sleep Apnea Occupations Pathway interactions Patients Periodicity Phenotype Prevalence Prospective Studies Proteomics Protocols documentation Publications Randomized Recurrence Research Research Project Grants Risk Risk Factors Role Safety Sampling Severities Site Sleep Sleep Apnea Syndromes Sleep Disorders Sleep Fragmentations Sleep disturbances Sleeplessness Societies Stroke Symptoms Techniques Treatment Efficacy United States National Institutes of Health base cardiovascular risk factor case control causal model clinical application clinical care clinical phenotype clinical practice clinical subtypes design disease heterogeneity disorder subtype epigenomics improved indexing individual patient insight metabolic abnormality assessment metabolomics mortality non-alcoholic fatty liver disease novel patient population patient subsets personalized diagnostics personalized medicine precision medicine pressure prognostic prospective response sample collection sleep regulation treatment response weight loss intervention

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项目摘要

ABSTRACT Obstructive sleep apnea (OSA) is a common disorder that is increasing in prevalence. OSA is known to have heterogeneous pathophysiology, with different subtypes, clinical consequence, and treatment responses among individual patients. A recent publication from the Sleep Research Society and National Heart, Lung and Blood Institute highlighted the potential clinical utility of quantitative OSA biomarkers identified using unbiased “omics” approaches.There are currently no established quantitative biomarkers that can be used to understand heterogeneity or inform clinical practice. Thus, the present study proposes to utilize metabolomic methods which reflect dynamic responses to hypoxia to identify metabolite signatures in OSA. The overarching hypothesis motivating this proposal is that blood-borne metabolite signatures that result from metabolic insults caused by the cyclical intermittent hypoxia, recurrent arousals and lack of deep sleep characteristic of OSA will provide a quantitative biomarker to better understand disease heterogeneity and inform clinical care. In Aim 1, we will differentiate OSA from non-OSA leveraging well- phenotyped samples carefully chosen from a large pool of patients from existing research projects (Aim 1A). Our preliminary suggest clear metabolite differences between patients with OSA and controls. Furthermore, we will leverage these existing samples to determine if established OSA symptom subtypes of disturbed sleep (e.g., insomnia), excessive sleepiness, and minimally symptomatic have distinct metabolomic profiles (Aim 1B) which will provide insights into identified differences in cardiovascular risk and support a precision medicine approach. These analyses utilizing banked samples are supported by a carefully designed prospective study of OSA patients before and after positive airway pressure (PAP) treatment in Aim 2. The study is designed to control for bias related to site-specific variance in sampling and data collection using state-of-the-art causal modeling techniques. As part of the prospective study, we will perform complementary analyses supporting metabolomic signatures (Aim 2A), determine a metabolomic signature that correlates with hours and days of PAP usage (Aim 2B) and evaluate whether the metabolomic changes with PAP treatment differ by obesity (Aim 2C) or symptom subtype (Aim 2D). In support of this Aim, preliminary data suggest metabolomic changes with PAP treatment.. Finally, in Aim 3 we will leverage existing samples of obese OSA subjects that were previously randomized to one of three treatments – weight-loss alone, PAP alone, or combined weight-loss and PAP. Differences in metabolomic changes among these three randomized groups will provide insights into the relative roles of obesity and cyclical intermittent hypoxia on metabolic responses and pathways. Ultimately, results from this proposal will provide comprehensive information on metabolomic signatures that can be utilized as quantitative biomarkers to further our understanding of OSA heterogeneity and inform clinical practice and personalized medicine among OSA patients. R01 Metabolomics of OSA - Page 1

抽象的阻塞性睡眠呼吸暂停（OSA）是一种常见的疾病，患病率正在增加。 OSA已知有具有不同亚型，临床后果和治疗的异质性病理生理学个别患者的反应。睡眠研究学会和国家的最新出版物心脏，肺和血液研究所强调了鉴定出定量OSA生物标志物的潜在临床实用性使用公正的“幻象”方法。目前没有建立的定量生物标志物可以是用于了解异质性或为临床实践提供依据。那是本研究的建议代谢组方法反映了对缺氧的动态反应，以鉴定OSA中的代谢产物特征。这促使该提议的总体假设是血源传播的代谢物特征来自周期性间歇性缺氧，复发性唤醒和缺乏深度的代谢侮辱 OSA的睡眠特征将提供定量生物标志物，以更好地了解疾病异质性并为临床护理提供信息。在AIM 1中，我们将使OSA与非OSA利用良好区别从现有研究项目（AIM 1A）的大量患者中精心挑选的表型样品（AIM 1A）。我们的初步表明OSA和对照患者之间的明显代谢物差异。此外，我们将利用这些现有样本来确定是否已建立的OSA症状亚型受干扰的睡眠（例如，失眠），过度的嗜睡和最小的症状具有独特的代谢性特征（AIM 1B）将提供有关确定心血管风险差异的洞察力，并支持精密医学方法。这些利用银行样品的分析得到了OSA经过精心设计的前瞻性研究的支持 AIM 2中正气道压力（PAP）治疗前后的患者。该研究旨在控制使用最先进的因果建模在采样和数据收集中与网站特定差异有关的偏差技术。作为前瞻性研究的一部分，我们将执行支持代谢组的完整分析签名（AIM 2A），确定与小时和几天使用情况相关的代谢组签名（AIM 2b）并评估肥胖症（AIM 2C）或症状不同的代谢组对PAP治疗的变化是不同的亚型（AIM 2D）。为了支持这一目标，初步数据表明PAP治疗的代谢组变化。最后，在AIM 3中，我们将利用以前被随机分配给的肥胖OSA受试者的现有样本三种治疗方法之一 - 单独减肥，单独使用PAP或结合减肥和PAP。差异这三个随机组之间的代谢组变化将提供有关相对作用的见解肥胖和周期性间歇性缺氧在代谢反应和途径上。最终，结果提案将提供有关代谢组签名的全面信息，可以用作定量生物标志物可以进一步了解OSA异质性并为临床实践提供信息和OSA患者的个性化药物。 R01 OSA的代谢组学 - 第1页