Imaging Epigenetic Dysregulation in Patients with Low Back Pain

腰痛患者表观遗传失调的影像学检查

• 批准号: 10375955
• 负责人: Hsiao-Ying Wey
• 金额: $ 189.93万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-26 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10375955
• 关键词: Absence of pain sensation; Acute; Address; Affect; Analgesics; Animal Model; Back; Binding; Biological Markers; Blood; Brain; Brain region; Cells; Chondrocytes; Chromatin; Chronic low back pain; Clinical; Complex; DNA; Detection; Development; Diagnosis; Differential Diagnosis; Disease; Drug Targeting; Environment; Enzymes; Epigenetic Process; Experimental Models; Family; Gene Expression; Gene Silencing; Genetic Code; Goals; HDAC1 gene; HDAC2 gene; Healthcare; Histone Acetylation; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone Deacetylation; Histones; Human; Human Volunteers; Image; Income; Inflammatory; Insula of Reil; Knee; Knowledge; Leg; Life Experience; Link; Lobule; Longitudinal Studies; Low Back Pain; Magnetic Resonance Imaging; Maintenance; Malignant Neoplasms; Maps; Measures; Mediating; Mental disorders; Monitor; Nerve; Neurodegenerative Disorders; Neuropathy; Outcome Measure; Pain; Patient Selection; Patients; Physical Function; Play; Positron-Emission Tomography; Pre-Clinical Model; Prefrontal Cortex; Process; Productivity; Proteins; Quality of life; Radiculopathy; Regulation; Research; Rodent; Rodent Model; Role; Scanning; Series; Signal Transduction; Somatosensory Cortex; Specificity; Spinal Cord; Symptoms; System; Techniques; Thalamic structure; Therapeutic; United States; Update; Validation; base; chronic pain; chronic pain patient; cohort; cost; density; epigenetic drug; follow-up; healing; imaging agent; imaging biomarker; imaging study; inflammatory pain; kinetic model; mental function; novel; osteoarthritis pain; pain chronification; pain model; pain patient; painful neuropathy; pre-clinical; preclinical study; prescription opioid; quantitative imaging; radiotracer; response; symptomatology; therapeutic target; treatment response; uptake; validation studies

Project Summary / Abstract Chronic pain is a complex disorder affects both physical and mental functioning and could compromise quality of life. Treatment for chronic pain is far from satisfactory because of the aversive effects associated with opioid medications. It is known that the development and maintenance of pain are mediated in the central nerves system; however, the pathophysiological causes contributing to pain remain to be determined. Neuroepigenetic mechanisms have been linked to the development and maintenance of pain through preclinical models of inflammatory and neuropathic pain. One family of epigenetic enzymes, known as histone deacetylases (HDACs), are being considered as therapeutic targets due to the analgesic responses achieved through HDAC inhibitors. Inhibition of HDACs leads to symptom amelioration in experimental models of pain. However, there is limited evidence about HDAC density concerning human pain across the entire brain. We have recently achieved a significant research goal by resolving a PET imaging agent, [11C]Martinostat, that selectively binds to a subset of HDAC enzymes. Our imaging studies to date, including more than 40 healthy human volunteers, have identified key features that make [11C]Martinostat a rare and promising HDAC probe including robust brain uptake and high specific binding. We are extremely excited to take a large step forward to develop [11C]Martinostat PET as a quantitative image biomarker for pain detection and diagnosis, with an ultimate goal of using [11C]Martinostat PET to monitor treatment responses. In this application, we propose a series of initial proof-of-concept clinical validation studies to evaluate if [11C]Martinostat PET is a sensitive biomarker to detect the typical (axial) chronic low back pain (cLBP). When successful, we will further explore the validity of using [11C]Martinostat PET to differentiate subtypes of pain by comparing [11C]Martinostat PET binding between axial cLBP with cLBP patients with radiculopathy. In addition, we plan to conduct a longitudinal study in sub-acute LBP patients (sLBP) to investigate whether there is unique imaging signature that differentiate patients who have convert to cLBP vs. those who recover from low back pain. We believe the research outlined in the proposal takes a robust and systematic approach to develop and validate [11C]Martinostat PET as a quantitative image biomarker for low back pain in patients. PET/MR imaging in humans with [11C]Martinostat will deliver answers to fundamental questions about chromatin modifying enzymes in the living human brain in a way that has not been possible until now. Importantly, using [11C]Martinostat to understand the alternation of HDAC expression in chronic pain patients will enable validation of an epigenetic drug target, refine patient selection based on HDAC expression, and facilitate proof of mechanism/target engagement in developing novel analgesics.

项目概要/摘要 慢性疼痛是一种复杂的疾病，影响身体和精神功能，并可能影响质量 的生活。由于与阿片类药物相关的厌恶作用，慢性疼痛的治疗远不能令人满意 药物。众所周知，疼痛的发生和维持是由中枢神经介导的 系统;然而，导致疼痛的病理生理学原因仍有待确定。神经表观遗传学 通过临床前模型，机制已与疼痛的发生和维持联系起来。 炎症性疼痛和神经性疼痛。表观遗传酶家族之一，称为组蛋白脱乙酰酶 (HDAC)，由于通过 HDAC 实现镇痛反应，被视为治疗靶点 抑制剂。 HDAC 的抑制可改善疼痛实验模型中的症状。然而，有 有关人类整个大脑疼痛的 HDAC 密度的证据有限。 我们最近通过解析 PET 显像剂 [11C]Martinostat 实现了一项重要的研究目标， 选择性结合 HDAC 酶的子集。迄今为止，我们的影像学研究包括超过 40 名健康人 人类志愿者已经确定了使 [11C]Martinostat 成为稀有且有前途的 HDAC 探针的关键特征 包括强大的大脑摄取和高特异性结合。我们非常高兴能够向前迈出一大步 开发 [11C]Martinostat PET 作为用于疼痛检测和诊断的定量图像生物标志物， 使用 [11C]Martinostat PET 监测治疗反应的最终目标。在这个应用中，我们提出了一个 一系列初步概念验证临床验证研究，以评估 [11C]Martinostat PET 是否敏感 检测典型（轴向）慢性腰痛（cLBP）的生物标志物。成功后我们将进一步探索 通过比较 [11C]Martinostat PET 来区分疼痛亚型的有效性 轴性 cLBP 与患有神经根病的 cLBP 患者之间的结合。此外，我们计划开展 亚急性腰痛患者 (sLBP) 的纵向研究，探讨是否存在独特的影像特征 区分已转为 cLBP 的患者与从腰痛中恢复的患者。 我们相信提案中概述的研究采用了稳健且系统的方法来开发和 验证 [11C]Martinostat PET 作为患者腰痛的定量图像生物标志物。 PET/MR 成像 在人类中使用 [11C]Martinostat 将解答有关染色质修饰的基本问题 以一种迄今为止不可能的方式在活人大脑中存在酶。重要的是，使用 [11C]Martinostat 了解慢性疼痛患者 HDAC 表达的变化将有助于 验证表观遗传药物靶标，根据 HDAC 表达细化患者选择，并促进证明 开发新型镇痛药的机制/目标参与。