MicroRNAs as Biomarkers for Obstructive Sleep Apnea

MicroRNA 作为阻塞性睡眠呼吸暂停的生物标志物

• 批准号: 10555810
• 负责人: ULYSSES J MAGALANG
• 金额: $ 49.63万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555810
• 关键词: Affect; Age; Area; Asthma; Biological Markers; Blood; Blood Pressure; Body mass index; Cardiovascular Diseases; Cholesterol; Chronic Obstructive Pulmonary Disease; Clinical; Code; Complement; Continuous Positive Airway Pressure; Data; Diabetes Mellitus; Disease; Drowsiness; Educational workshop; Effectiveness; Enrollment; Etiology; Exclusion Criteria; Foundations; Goals; Hour; Hypertension; Hypoxia; Individual; International; Literature; Lung diseases; Measurement; Measures; Medicine; Methods; MicroRNAs; Monitor; Obstructive Sleep Apnea; Participant; Pathogenesis; Patients; Persons; Predictive Value; Process; Proteins; RNA; Reporting; Research; Risk; Risk Factors; Sample Size; Sampling; Severities; Severity of illness; Sleep; Sleep Disorders; Sleep Fragmentations; Sleep disturbances; Sleeplessness; Symptoms; Techniques; Testing; Therapeutic; Translations; Treatment Efficacy; United States National Institutes of Health; Untranslated RNA; Validation; biomarker identification; cardiovascular risk factor; case control; clinical risk; clinical translation; comorbidity; effectiveness measure; efficacy evaluation; improved; microRNA biomarkers; next generation sequencing; polygenic risk score; population based; positive airway pressure; precision medicine; predictive signature; prognostic; prognostic value; programs; recruit; response; risk stratification; sex; sleep regulation; specific biomarkers; treatment response

ABSTRACT Identification of biomarkers of the severity of sleep-related conditions and the effectiveness of therapies was recently presented as the number one critical opportunity in the 2021 Sleep Research Plan from the National Institutes of Health and National Center on Sleep Disorders Research (NCSDR). While obstructive sleep apnea (OSA) is common, there are limited biomarkers for identification and management of the condition. Specific use cases for an OSA biomarker include: (i) improving case identification, (ii) monitoring efficacy of therapy, and (iii) providing prognostic value with respect to who will get particular consequences or how individuals respond to continuous positive airway pressure (CPAP) treatment. While different approaches can be used to define biomarkers, this project will focus on microRNAs, which have very recently been shown to be promising biomarkers in OSA. MicroRNAs are small non-coding RNAs that alter the translation of protein coding RNA. Their expression is dynamic and altered by many challenges, such as hypoxia. Expression of all microRNAs in blood can be assessed by sequencing all short RNAs. Prior studies, albeit with small sample sizes, suggest differences in microRNA expression between OSA cases and controls and that differences in microRNA expression can identify individuals with OSA who will show larger blood pressure responses to CPAP treatment. Using complementary sequencing approaches and clinically-feasible quantitative PCR (qPCR), we propose to validate and extend these initial observations. First, we will seek biomarkers that are specific to OSA by evaluating differences in microRNA profiles between cases with OSA and controls without OSA matched for age, sex, and body mass index and without other underlying conditions that could independently affect microRNA expression. While identifying microRNAs specific to OSA is important, it is also useful to determine microRNAs useful for improving OSA case identification beyond known clinical risk factors. Thus, this project will enroll a larger case-control sample with minimal exclusion criteria in which to assess the predictive value of differences in microRNA expression. To understand the utility of microRNAs as treatment-related biomarkers, cases with OSA will be studied before and after 6 months of CPAP. We anticipate that some microRNAs specific to OSA will normalize with CPAP treatment, thus providing an objective measure of effectiveness. In all OSA cases, we will assess 24-hour ambulatory blood pressure to validate and extend recent reports of a microRNA signature that predicts blood pressure response to CPAP. We will conduct robust validation for all biomarkers. First, using the same samples sequenced in discovery analyses, we will perform analytical validation via clinically-feasible qPCR techniques. Independent validation of microRNA signatures will be done in new samples, including cases and controls from Project 01. Moreover, the relative utility of microRNAs and other signatures developed in the Program, such as polygenic risk scores, will be assessed. Overall, this Project is directly aligned with the stated research objectives of the NCSDR and the specific goals of this Program Project.

抽象的 识别睡眠相关疾病严重程度和治疗有效性的生物标志物 最近被列为国家 2021 年睡眠研究计划中的头号关键机遇 健康研究所和国家睡眠障碍研究中心 (NCSDR)。当阻塞性睡眠呼吸暂停 (OSA) 很常见，但用于识别和管理该病症的生物标志物有限。具体用途 OSA 生物标志物的病例包括：(i) 改进病例识别，(ii) 监测治疗效果，以及 (iii) 提供关于谁将受到特定后果或个人如何应对的预测价值 持续气道正压通气（CPAP）治疗。虽然可以使用不同的方法来定义 生物标记物，该项目将重点关注 microRNA，它最近被证明是有前途的 OSA 中的生物标志物。 MicroRNA 是小的非编码 RNA，可以改变蛋白质编码 RNA 的翻译。 它们的表达是动态的，并会因缺氧等许多挑战而改变。所有 microRNA 的表达 可以通过对所有短 RNA 进行测序来评估血液。先前的研究表明，尽管样本量较小 OSA 病例和对照之间 microRNA 表达的差异以及 microRNA 的差异 表达可以识别患有 OSA 的个体，这些个体对 CPAP 治疗表现出更大的血压反应。 使用互补测序方法和临床可行的定量 PCR (qPCR)，我们建议 验证并扩展这些初步观察结果。首先，我们将通过以下方式寻找特定于 OSA 的生物标志物： 评估患有 OSA 的病例和未患 OSA 的对照组之间 microRNA 谱的差异，并与年龄相匹配， 性别和体重指数，并且没有其他可能独立影响 microRNA 的潜在条件 表达。虽然识别 OSA 特异性的 microRNA 很重要，但确定 microRNA 也很有用 对于改善已知临床危险因素之外的 OSA 病例识别很有用。因此，本项目将招收一名 具有最小排除标准的更大病例对照样本，用于评估差异的预测价值 在微小RNA表达中。为了了解 microRNA 作为治疗相关生物标志物的效用，案例 OSA 将在 CPAP 治疗前后 6 个月进行研究。我们预计一些特定于 OSA 的 microRNA 将通过 CPAP 治疗恢复正常，从而提供客观的有效性衡量标准。在所有 OSA 案例中，我们 将评估 24 小时动态血压，以验证和扩展最近的 microRNA 特征报告 预测血压对 CPAP 的反应。我们将对所有生物标志物进行严格的验证。首先，使用 在发现分析中对相同的样本进行测序，我们将通过临床可行的方法进行分析验证 qPCR 技术。将对新样本（包括病例）中的 microRNA 特征进行独立验证 和项目 01 中的对照。此外，microRNA 和其他特征的相对效用在 将评估多基因风险评分等计划。总体而言，该项目与所述的直接一致 NCSDR 的研究目标和本计划项目的具体目标。