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

项目总结 最常见且代价高昂的慢性疼痛之一是下腰痛(LBP)，它会产生更多的 残疾比任何其他情况都要好。高达39%的急性LBP患者报告慢性LBP(疼痛 持续3个月)和长期残疾2年或更长时间。增加了对机械的理解 从急性到慢性LBP的转变将使我们能够在过渡期的早期和新的 在预防和/或更好地管理慢性LBP的关键机会窗口的治疗目标。在这项研究中， 我们将测试这一假设，即神经生理和基因表达差异可以用来建立 一个预测模型，将定义慢性LBP表型和转录组，并识别这些LBP 将从急性疼痛表型转变为慢性疼痛表型的患者。我们将前瞻性地跟踪一组 380名LBP患者和40名健康对照(与LBP患者进行比较并追踪基因表达稳定性 随着时间的推移)在首次就诊以报告LBP之后的两年。我们将严格表型 参与者，包括神经生理因素的测量，并分析基线和 第一年、18个月和24个月有规律的间隔。我们将通过两个具体的途径来实现这些目标 目的：目的1：检验急性疼痛向慢性疼痛转变的神经生理学预测因子 首次就诊后LBP报告的基线和随时间变化。我们将在以下时间招募参与者 术后6周、8周、10周、12周、16周、20周、24周和52周，以及发病后18个月和24个月。在… 与抽血对应的时间点进行rna-seq我们将进行神经生理测试 表征周围感觉神经功能、时间总和(发条)和条件性痛觉调制 (下行抑制性痛觉调制系统的完整性)。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：检验差异的假设 MHC基因在基线和长期的表达将与慢性疾病的风险相关 疼痛，而已知疼痛基因的差异表达将定义慢性LBP转录组。在这 目的：我们将在基线、6、12、24、52周和2年从全血中提取总RNA进行测序。 我们将研究三组(n=20名健康人群)极端表型的基因表达变化的差异 受试者，在六个时间点的每个时间点，急性LBP和慢性LBP各50例。除了生物标记物 鉴定，我们将对差异表达基因进行无偏向通路分析，以获得 对慢性疼痛预防和/或管理的潜在新治疗目标的机械性洞察。这 这项研究与NINR的战略计划和使命、国家疼痛战略、国际移民组织报告和 美国国立卫生研究院的治愈计划，以确定慢性疼痛风险的生物标记物和治疗性疼痛目标。

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.