Neurophysiological and transcriptomic predictors of chronic low back pain: towards precision pain management (NEAT Study)

慢性腰痛的神经生理学和转录组学预测因素：实现精准疼痛管理（NEAT 研究）

• 批准号: 10194615
• 负责人: SUSAN G DORSEY
• 金额: $ 62.02万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-23 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10194615
• 关键词: Accounting; Acute; Age; Americas; Antigen Presentation; Area; Biological Assay; Biological Markers; Blood; Chronic; Chronic low back pain; Clinic Visits; Clinical; Data; Degenerative polyarthritis; Demographic Factors; Enrollment; Environmental Wind; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Transcription; Goals; Helping to End Addiction Long-term; Histocompatibility; Immune; Individual Differences; Institute of Medicine (U.S.); Intervention; Link; Liver diseases; Low Back Pain; Measurement; Methodology; Migraine; Mission; Modeling; Nerve Degeneration; Pain; Pain management; Participant; Pathway Analysis; Pathway interactions; Patients; Peripheral; Persistent pain; Phenotype; Predictive Factor; Prevention; Psychosocial Factor; Public Health; Quality of life; Questionnaires; RNA; Reporting; Risk; Sensory; Strategic Planning; Structural defect; System; Testing; Therapeutic; Time; Tissue-Specific Gene Expression; United States; United States National Institutes of Health; Whole Blood; Work; afferent nerve; biomarker development; biomarker identification; biomarker signature; central sensitization; chronic pain; chronic painful condition; cohort; conditioned pain modulation; cost; differential expression; disability; early detection biomarkers; gene discovery; genome wide association study; genomic locus; improved; insight; neurophysiology; new therapeutic target; pain patient; pain relief; pain score; pain sensitivity; phenotypic biomarker; predictive marker; predictive modeling; prevent; prospective; psychosocial; sex; somatosensory; transcriptome; transcriptome sequencing; transcriptomics

PROJECT SUMMARY One of the most common and costly chronic pain conditions is low back pain (LBP), which produces more global disability than any other condition. Up to 39% of patients with an acute LBP episode report chronic LBP (pain lasting >3 months) and long-term disability for 2 years or longer. Increased mechanistic understanding of the transition from acute to chronic LBP will enable us to identify biomarkers early in the transition period and new therapeutic targets at critical windows of opportunity to prevent and/or better manage chronic LBP. In this study, we will test the hypothesis that neurophysiological and gene expression differences can be used to build a predictive model that will define the chronic LBP phenotype and transcriptome and identify those LBP patients who will transition from acute to chronic pain phenotypes. We will prospectively follow a cohort of 380 LBP patients and 40 healthy controls (for comparison with LBP patients and to track gene expression stability over time) for two years following the initial clinic visit for report of LBP. We will rigorously phenotype the participants, including measurement of neurophysiological factors, and analyze gene expression at baseline and regular intervals during the first year and at 18 and 24 months. We will accomplish these goals via two specific aims: Aim 1: To examine neurophysiological predictors of the transition from acute to chronic pain at baseline and over time following initial clinic visit for report of LBP. We will enroll participants at time of initial LBP and follow them 6, 8, 10, 12, 16, 20, 24, and 52 weeks, as well as 18 and 24 months’ post onset. At timepoints that correspond with blood draws for RNA-seq we will conduct neurophysiological testing to characterize peripheral sensory nerve function, temporal summation (wind up) and conditioned pain modulation (intactness of the descending inhibitory pain modulatory system). At other timepoints, participants will fill out online questionnaires about pain and psychosocial constructs. Aim 2: To test the hypothesis that differential expression of MHC locus genes at baseline and over time will be associated with the risk for chronic pain, while differential expression of known pain genes will define the chronic LBP transcriptome. In this aim, we will isolate total RNA from whole blood for sequencing at baseline and 6, 12, 24, 52 weeks, and 2 years. We will examine how changes in gene expression differs in extreme phenotypes from three groups (n=20 healthy participants, n=50 acute LBP, n=50 chronic LBP) at each of the six timepoints. In addition to biomarker identification, we will conduct non-biased pathway analysis of the differentially expressed genes to gain mechanistic insight into potential novel therapeutic targets for chronic pain prevention and/or management. This study is highly aligned with NINR’s strategic plan and mission, the National Pain Strategy, IOM report, and the NIH’s HEAL Initiative to identify biomarkers of the risk for chronic pain and therapeutic pain targets.

项目概要 最常见和最昂贵的慢性疼痛之一是腰痛 (LBP)，它在全球范围内产生了更多 高达 39% 的急性腰痛发作患者报告为慢性腰痛（疼痛）。 持续 > 3 个月）和 2 年或更长时间的长期残疾 增加对机制的了解。 从急性腰痛到慢性腰痛的过渡将使我们能够在过渡期的早期识别生物标志物和新的生物标志物。 在这项研究中，目标是预防和/或更好地管理慢性腰痛的关键机会窗口。 我们将测试神经生理学和基因表达差异可以用来建立的假设 定义慢性腰痛表型和转录组并识别这些腰痛的预测模型 我们将前瞻性地跟踪一组将从急性疼痛表型转变为慢性疼痛表型的患者。 380 名 LBP 患者和 40 名健康对照（用于与 LBP 患者进行比较并追踪基因表达稳定性 在初次就诊以获取 LBP 报告后的两年内，我们将严格对 LBP 进行表型分析。 参与者，包括测量神经生理学因素，并分析基线和基因表达 在第一年以及第 18 个月和第 24 个月定期进行，我们将通过两个具体目标来实现这些目标。 目的： 目标 1：检查从急性疼痛转变为慢性疼痛的神经生理学预测因素 基线和初次临床访问报告后的一段时间，我们将在 时招募参与者。 初始 LBP 并在发病后 6、8、10、12、16、20、24 和 52 周以及 18 和 24 个月进行随访。 与 RNA-seq 抽血相对应的时间点，我们将进行神经生理学测试 表征周围感觉神经功能、时间总和（结束）和条件性疼痛调制 （下行抑制性疼痛调节系统的完整性）在其他时间点，参与者将填写。 关于疼痛和心理社会结构的在线调查问卷 目标 2：检验差异化的假设。 MHC 位点基因在基线和随着时间的推移的表达将与慢性病的风险相关 疼痛，而已知疼痛基因的差异表达将定义慢性 LBP 转录组。 我们的目标是从全血中分离总 RNA，以便在基线、6、12、24、52 周和 2 年时进行测序。 我们将研究三组​​（n = 20 名健康人）的极端表型中基因表达的变化有何不同。 参与者，n=50 名急性腰痛，n=50 名慢性腰痛）在六个时间点的每个时间点。 鉴定后，我们将对差异表达基因进行无偏的通路分析，以获得 对慢性疼痛预防和/或管理的潜在新治疗靶点的机制洞察。 该研究与 NINR 的战略计划和使命、国家疼痛战略、IOM 报告以及 NIH 的 HEAL 计划旨在识别慢性疼痛风险的生物标志物和治疗疼痛目标。