Identifying novel therapeutic targets for chronic neck pain: RNA-sequencing in human painful atlanto-axial arthropathy

项目总结/摘要 背景慢性颈部疼痛是世界范围内残疾的主要决定因素之一，是导致 目前阿片类药物的流行，以及巨大的医疗保健支出的原因。我们目前还不了解 颈部病变组织中的哪种分子机制产生了引起疼痛的信号 疾病负担。这种知识上的差距阻碍了有效的、机制特异性疗法的发展。 瞄准我们计划对接受手术的慢性颈部疼痛患者的组织进行RNA测序， 然后使用计算生物学和患者表型分析技术， 导致慢性颈部疼痛的药物 Approach.我们将招募因寰枢椎引起的慢性颈部疼痛而接受手术的患者， 关节这个关节位于脊柱两侧的第一和第二颈椎之间，是一个常见的关节。 关节炎的部位。我们还将招募因骨折引起的急性疼痛而接受相同手术的患者。期间 在手术中，我们将从关节和背根神经节（DRG）取样组织，其中神经供应 关节位于。这些组织将在慢性疼痛患者的手术过程中被移除，独立于 书房对于急性疼痛患者，我们将使用我们现有的无疼痛患者背根神经节数据库。 我们将对两侧的样本进行RNA测序，以比较疼痛和非疼痛组织的组织。 痛苦的一面。我们将记录临床疼痛特征，测量疼痛敏感性， 用针刺、压力和冷刺激评估神经功能。我们还将使用计算生物学方法 来评估病变组织是如何与神经系统相互作用从而引发疼痛的。这些方法将使我们能够 确定与疼痛结果相关的目标。 目的1：研究急、慢性疼痛关节组织和背根神经节的RNA表达谱 确定慢性颈痛组织中差异表达的基因。 目的2：使用计算生物学技术来确定病理分子如何起源于关节 组织与DRG神经元上的特定受体相互作用以产生疼痛信号。 目的3：确定关节和神经中RNA测序结果与临床表现的相关性。 颈部疼痛，疼痛敏感性和神经功能的表现。这将提供信息， 关节和神经的变化对疼痛特别重要。 冲击该项目将使前所未有的分子途径，特别是相关的鉴定 慢性颈痛我们的工作将创建一个独特的分子靶点图，用于未来治疗慢性 颈部疼痛完全基于人类分子神经科学。

PROJECT SUMMARY / ABSTRACT Background. Chronic neck pain is one of leading determinants of disability worldwide, a major contributor to the current opioid epidemic, and the cause of enormous health care expenditures. We currently do not understand which molecular mechanisms in the diseased tissues of the neck generate the painful signals that cause this disease burden. This gap in knowledge impedes development of effective, mechanism-specific therapeutics. Aim. We plan to use RNA sequencing on tissues taken from chronic neck pain patients undergoing surgery and then use computational biology and patient phenotyping techniques to gain better insight into molecular drivers that cause chronic neck pain. Approach. We will recruit patients undergoing surgery for chronic neck pain stemming from the atlanto-axial joint. This joint is located between the 1st and 2nd cervical vertebrae on both sides of the spine and is a common site of arthritis. We will also recruit patients undergoing the same surgery for acute pain due to fractures. During surgery, we will sample tissues from the joint and the dorsal root ganglion (DRG), in which the nerves supplying the joint are located. These tissues would be removed during surgery in chronic pain patients, independent of the study. For acute pain patients we will use our existing dorsal root ganglion database of people with no pain. We will perform RNA sequencing on samples from both sides, in order to compare tissues from painful and non- painful side of the same individual. We will record clinical pain characteristics, measure pain sensitivity and assess nerve function using pinprick, pressure and cold stimuli. We will also use computational biology methods to assess how diseased tissue interacts with the nervous system to drive pain. These methods will allow us to identify targets that are related to pain outcomes. Aim 1: To determine the RNA expression profile of the joint tissues and DRG from acute and chronic pain patients to determine genes that are differentially expressed in chronic neck pain tissues. Aim 2: To use computational biology techniques to determine how pathological molecules originating in the joint tissues interact with specific receptors on neurons of the DRG to generate the pain signal. Aim 3: To determine the association of RNA sequencing findings in the joint and nerves with clinical manifestations of neck pain, pain sensitivity and nerve function. This will provide information on which molecular changes at the joint and nerves are of specific importance to pain. Impact. The project will enable unprecedented identification of molecular pathways specifically associated with chronic neck pain. Our work will create a unique map of molecular targets for the future treatment of chronic neck pain based entirely on human molecular neuroscience.