Imaging Epigenetic Dysregulation in Patients with Low Back Pain

项目总结/摘要 慢性疼痛是一种复杂的疾病，影响身体和精神功能，并可能损害质量 生命由于阿片类药物的不良反应，慢性疼痛的治疗远不能令人满意 药物治疗已知疼痛的发展和维持是在中枢神经中介导的 然而，导致疼痛的病理生理原因仍有待确定。神经后生的 通过临床前模型， 炎性和神经性疼痛。一个表观遗传酶家族，称为组蛋白脱乙酰酶 由于通过HDAC实现的镇痛反应，HDAC被认为是治疗靶点 抑制剂的HDAC的抑制导致疼痛实验模型中的症状改善。但 关于HDAC密度与整个大脑中人类疼痛有关的证据有限。 我们最近通过解析PET成像剂[11 C]Martinostat实现了一个重要的研究目标， 选择性地结合HDAC酶的子集。迄今为止，我们的成像研究，包括40多个健康 人类志愿者已经确定了使[11 C]Martinostat成为罕见且有前途的HDAC探针的关键特征 包括强的脑摄取和高特异性结合。我们非常兴奋地向前迈出了一大步 开发[11 C]Martinostat PET作为疼痛检测和诊断的定量图像生物标志物， 使用[11 C]Martinostat PET监测治疗反应的最终目标。在本申请中，我们提出了一种 一系列初步概念验证临床验证研究，以评估[11 C]Martinostat PET是否是一种敏感的 生物标志物来检测典型的（轴向）慢性腰痛（cLBP）。成功后，我们将进一步探索 通过比较[11 C]Martinostat PET，使用[11 C]Martinostat PET区分疼痛亚型的有效性 轴向cLBP与神经根病患者cLBP之间的结合。此外，我们亦计划进行一项 在亚急性LBP患者（sLBP）中进行的纵向研究，以调查是否存在独特的成像特征 这将区分转换为cLBP的患者与从腰痛中恢复的患者。 我们认为，提案中概述的研究采取了一种强有力的系统方法， 验证[11 C]Martinostat PET作为患者腰痛的定量图像生物标志物。PET/MR成像 [11 C]Martinostat将为染色质修饰的基本问题提供答案 酶在人类大脑中的作用，这是迄今为止不可能的。重要的是，使用 [11 C]Martinostat了解慢性疼痛患者中HDAC表达的变化将使 验证表观遗传药物靶点，根据HDAC表达完善患者选择， 在开发新型镇痛药中的机制/靶点参与。

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.