Imaging Epigenetic Dysregulation in Patients with Low Back Pain

项目摘要/摘要 慢性疼痛是一种复杂的疾病，会影响身体和精神功能，并可能影响质量 生活的一部分。慢性疼痛的治疗远非令人满意，因为阿片类药物会产生不良反应。 药物。众所周知，疼痛的发生和维持是由中枢神经调节的 然而，导致疼痛的病理生理原因仍有待确定。神经表观遗传学 机制与疼痛的发生和维持有关，通过临床前模型 炎症性和神经性疼痛。一个表观遗传酶家族，称为组蛋白脱乙酰酶 (HDAC)，由于通过HDAC实现的止痛反应，正被认为是治疗的靶点 抑制剂。抑制HDACs可改善实验性疼痛模型的症状。然而，在那里 有关人类整个大脑疼痛的HDAC密度的证据有限。 我们最近通过分解一种PET显像剂[11C]Martinostat，实现了一个重要的研究目标 选择性地与HDAC酶的一个子集结合。到目前为止，我们的成像研究包括40多名健康 人类志愿者已经确定了使[11C]Martinostat成为一种罕见且有前途的HDAC探测器的关键特征 包括强大的大脑摄取和高度特异的结合。我们非常兴奋地向前迈进了一大步 开发[11C]Martinostat PET作为疼痛检测和诊断的定量图像生物标记物，具有 使用[11C]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 评估[11C]马替诺他汀PET是否敏感的一系列初步概念验证临床研究 生物标志物，用于检测典型的(轴性)慢性下腰痛(CLBP)。成功后，我们将进一步探索 应用[11C]马替诺他汀PET鉴别疼痛亚型的有效性 轴性cLBP与神经根病患者cLBP的结合。此外，我们计划进行一项 亚急性LBP患者的纵向研究：是否有独特的影像征象 这将转换为cLBP的患者与那些从下腰痛中恢复的患者区分开来。 我们相信，建议中概述的研究采用了一种稳健和系统的方法来开发和 验证[11C]Martinostat PET作为患者下腰痛的定量图像生物标记物。PET/MR成像 在患有[11C]的人类中，Martinostat将为染色质修饰的基本问题提供答案 在活着的人脑中，酶以一种直到现在还不可能实现的方式。重要的是，使用 [11C]马替诺他了解慢性疼痛患者HDAC表达的变化将使 验证表观遗传药物靶点，改进基于HDAC表达的患者选择，并促进证据 在开发新型止痛药方面的机制/目标参与。

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.