Plasma metabolite and proteome signatures for migraine classification

用于偏头痛分类的血浆代谢物和蛋白质组特征

• 批准号: 10219629
• 负责人: Daniel Ian Chasman
• 金额: $ 206.5万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219629
• 关键词: Affect; Analgesics; Auras; Biological Assay; Biological Markers; Blood Vessels; Blood specimen; Cardiovascular Diseases; Ceramides; Characteristics; Classic Migraine; Classification; Clinical; Clinical Trials; Common Migraine; Data; Diagnosis; Diagnostic; Diet Habits; Disease; Etiology; Freezing; Frequencies; Functional disorder; Genetic; Genome; Goals; Headache; Headache Disorders; Health; Heterogeneity; Individual; Inflammatory; International; Investigation; Measurement; Measures; Mendelian randomization; Metabolic; Methods; Migraine; Migraine Variants; Motor; Nausea; Opioid; Pain; Participant; Perception; Phase; Phonophobias; Photophobia; Physical activity; Plasma; Population; Predisposition; Prevalence; Proteins; Proteome; Proteomics; Qualifying; Recurrence; Reporting; Research; Resolution; Risk Marker; Sampling; Sampling Studies; Sensory; Sphingolipids; Statistical Models; Stroke; Symptoms; Therapeutic; Uncertainty; Validation; Visual; Woman; Women' s Group; base; biomarker signature; cohort; diagnostic biomarker; experience; follow-up; genetic variant; improved; men; new therapeutic target; novel therapeutics; population based; prophylactic; proteomic signature; recruit; response; treatment optimization; validation studies; whole genome; years lived with disability

Project Summary/Abstract Migraine is a debilitating pain condition and ranks globally in the top five for years lived with disability. Approximately 15% of the general US population experiences migraine, with women afflicted approximately twice as often as men. Migraine is currently diagnosed by a qualifying recurrence of symptoms, including aura, formally codified by the International Classification of Headache Disorders. However, the lack of established, explicitly quantitative biomarkers for migraine, especially causal biomarkers, is widely viewed as a critical impediment to optimizing and developing therapeutic strategies, and to advancing understanding of migraine pathophysiology. Our preliminary data suggest that such causal plasma-based biomarkers exist and can be identified. In addition, formally diagnosed migraine may present with or without aura and a diversity of other symptoms, all equally qualifying for migraine, suggesting heterogeneity in migraine etiology. Thus, a second but equally important goal for a quantitative migraine biomarker, especially a causal biomarker, is to resolve possible subclasses of migraine, which may be used in treatment decisions. We propose an investigation that is responsive to PAR-19-315 through a goal of identifying and validating plasma-based biomarkers diagnostic of migraine and its potential subclasses. During the R61 phase of the research, we will measure a comprehensive panel of >1300 plasma metabolites and 92 vascular related proteins among three groups of women from the Women’s Genome Health Study (WGHS): those with active migraine, non-migraine headache, and no headache symptoms. In these data, we will use state-of-the-art statistical modeling to identify plasma-based metabolite and protein signatures of migraine that formally discriminate individuals with active migraine from those never reporting headache and also those reporting non-migraine headache as well as among sub-classes of migraine defined by specific migraine symptoms, e.g. aura. Using existing genetic data, we will apply a genetic instrumental variable method termed “Mendelian Randomization” to assess whether these metabolite signatures may have causal effects on migraine. During the R33 phase, we will develop and apply a validated assay(s) targeting the metabolite(s) and/or protein(s) identified in the R61 to perform an initial validation study our biomarker signature within a new cohort of men and women recruited for this project. We anticipate that findings from the proposed research have the potential to help refine the analysis of response in clinical trials, optimize current prophylactic strategies, suggest new therapeutics, and resolve uncertainty in assignment of diagnostic aura status and other potential sub-classes of migraine.

项目摘要/摘要 偏头痛是一种令人虚弱的疼痛状况，多年来一直位居全球前五名。 大约15%的美国总人口患有偏头痛，其中大约有女性 是男性的两倍。偏头痛目前被诊断为符合条件的症状复发，包括先兆， 正式编入《国际头痛疾病分类》。然而，缺乏成熟的， 偏头痛的明确定量生物标记物，特别是因果生物标记物，被广泛认为是关键 阻碍优化和开发治疗策略，并促进对偏头痛的理解 病理生理学。我们的初步数据表明，这种基于血浆的因果生物标志物是存在的，而且可能是 确认身份。此外，正式诊断的偏头痛可能有或没有先兆和其他多种症状。 症状，都同样符合偏头痛的条件，这表明偏头痛的病因是不同的。因此，一秒钟 但是，定量偏头痛生物标记物，特别是因果生物标记物，同样重要的目标是解决 偏头痛的可能亚型，可用于治疗决策。 我们建议进行一项针对PAR-19-315的调查，目的是确定和 验证基于血浆的生物标志物对偏头痛及其潜在亚类的诊断。在R61阶段 在这项研究中，我们将测量一组全面的&gt；1300种血浆代谢物和92种血管相关物质 来自女性基因组健康研究(WGHS)的三组女性中的蛋白质：那些活跃的 偏头痛，非偏头痛，无头痛症状。在这些数据中，我们将使用最先进的 统计建模以确定偏头痛的血浆代谢物和蛋白质特征 将活动期偏头痛患者与从未报告头痛的人和报告头痛的人区分开来 非偏头痛以及由特定偏头痛症状定义的偏头痛的亚类，例如 气场。利用现有的遗传数据，我们将应用一种名为孟德尔的遗传工具变量方法 随机“评估这些代谢物特征是否可能对偏头痛有因果影响。在.期间 在R33阶段，我们将开发并应用针对代谢物(S)和/或蛋白质(S)的有效检测方法(S) 在R61中确定以在新的男性队列中执行我们的生物标志物签名的初步验证研究 以及为这个项目招募的女性。 我们预计，拟议研究的结果有可能有助于完善对 临床试验中的反应，优化当前的预防策略，建议新的治疗方法，并解决 偏头痛的诊断先兆状态和其他潜在亚类的分配存在不确定性。