Neuroepigenetic mechanisms of chronic low back pain using histone deacetylases PET imaging

项目摘要/摘要 组蛋白脱乙酰酶(HDAC)是一种染色质修饰蛋白，已成为一种重要的 引导人们了解中枢神经系统功能障碍。到目前为止，HDAC的表达已经在一小部分 来自健康和受脑部疾病影响的患者的死后脑组织样本，包括 阿片成瘾(海洛因)、精神分裂症、抑郁症、阿尔茨海默病，并提供证据表明 在大脑皮层和一些皮质下区域(如腹侧被盖区)，HDACs的表达可能起到 在脑部疾病的基础上起着核心作用。动物模型研究支持HDAC的表达 是神经发育/可塑性、衰老、认知、学习和记忆的重要调节因子。此外， 靶向HDAC的合成小分子已被证明可以使HDAC的表达水平正常化，并 减轻动物的疾病相关行为。这些临床前证据强调了极有必要 提高对HDAC表达、脑功能和疾病之间关系的理解 活体人脑的发病机制。 我们最近通过分解一种PET显像剂[11C]Martinostat实现了一个主要的研究目标 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成为罕见且有前途的CNS HDAC的关键特征 探针包括强大的脑摄取和高特异性结合。我们非常兴奋地迈出了一大步 通过可视化大脑中的HDAC来了解慢性疼痛患者的神经调节障碍。作为一名 为了实现这一目标，我们建议研究[11C]马替诺他汀在慢性阻塞性肺疾病患者中的分布和可用性。 服用和不服用处方阿片类药物的下腰痛患者。与健康对照组比较， 我们可以将[11C]Martinostat结合的变化归因于慢性疼痛。此外，我们的研究设计允许 进一步研究处方阿片类药物和性别差异对HDAC可获得性的影响。我们的团队 在马蒂诺斯中心，是世界上少数几个可以直接将基础科学进步转化为 对人类系统的了解。 我们在18-79岁人群中对[11C]马替诺他汀的初步数据有力地支持了这一可行性和 我们建议在成年健康受试者中进行临床影像检查的成功。应用于人类的PET/MR成像 [11C]Martinostat将回答有关生物中染色质修饰酶的基本问题 人类大脑的一种方式，这是直到现在才可能实现的。重要的是，使用[11C]Martinostat来理解 慢性疼痛患者中HDAC表达的变化将使表观遗传药物靶点的验证成为可能， 根据HDAC表达优化患者选择，并促进机制/目标参与的证明 开发新型止痛药。

Project Summary / Abstract Histone deacetylase (HDAC) enzymes are chromatin-modifying proteins that have emerged as an important lead in understanding CNS dysfunction. To date, HDAC expression has been measured in a small number of postmortem brain tissue samples from healthy and diseased patients affected by brain disorders including opioid addiction (heroin), schizophrenia, depression, Alzheimer’s disease and provides evidence that altered expression of HDACs in cortex and some subcortical regions (such as the ventral tegmental area), may play a central role in the underpinnings of brain disease. Research in animal models supports that HDAC expression is a critical mediator of neural development/plasticity, aging, cognition, learning and memory. Further, synthetic small molecules targeting HDACs have been shown to normalize HDAC expression levels and alleviate disease-related behaviors in animals. These preclinical evidence underscoring the great need to improve understanding of the relationship between HDAC expressions, brain function and disease pathogenesis in the living human brain. We have recently achieved a major 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 CNS HDAC probe including robust brain uptake and high specific binding. We are extremely excited to take a large step forward in understanding neural dysregulation in chronic pain patients by visualizing HDAC in the brains. As a first towards this goal, we propose to investigate the distribution and availability of [11C]Martinostat in chronic low back pain patients with and without taking prescription opioids. When comparing to healthy control group, we can attribute changes in [11C]Martinostat binding related to chronic pain. In addition, our study design allow further investigations on the effects of prescription opioids and sex differences on HDACs availability. Our team at the Martinos Center is one of few in the world that can directly translate basic science advancements to knowledge of the human system. Our preliminary data on [11C]Martinostat in humans age 18-79 years strongly supports the feasibility and success of our proposal for clinical imaging in healthy subjects in adulthood. 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.