Epigenetic Mechanisms in Alcohol Use Disorder quantified by non-invasive PET imaging

摘要/摘要 越来越多的证据表明，组蛋白乙酰化等表观遗传过程可能在 在酒精诱导的基因调控和行为中的作用。到目前为止，在动物身上的研究表明 组蛋白脱乙酰酶(HDACs)，至少是HDAC2和HDAC3，可以诱导组蛋白相关的表观遗传学改变 乙醇处理后。此外，几项研究表明，HDAC抑制剂可用于 对抗乙醇诱导的行为和乙醇诱导的HDAC水平的变化。 我们最近通过开发一种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。[11C]马丁诺斯特一直被充分描述为一部小说和 通过啮齿动物、非人灵长类(NHP)成像进行表观遗传学研究的首个PET放射性示踪剂 并试行健康的人体成像。我们非常兴奋地在理解上向前迈进了一大步 通过观察酒精使用中健康和功能障碍的人脑中的HDAC在酒精中毒中的表观遗传学作用 精神障碍(AUD)患者。 与我们的多学科团队和强大的合作伙伴一起，我们正在通过 R21/R33机制用于这项高风险、高回报的研究，以表征密钥的密度和分布 应用我们的新PET对健康受试者和酒精中毒患者的脑内HDAC进行检测 成像探头。 我们关于人体[11C]马替诺他汀的初步数据有力地支持了我们的临床成像计划的成功 在健康受试者(目标1)和AUD患者(目标2和目标3)中处于R21/R33期。PET-MR成像技术的应用 使用[11C]Martinostat的人类将回答有关染色质修饰的基本问题 活着的人脑中的酶，这是到目前为止还不可能的，并有助于证明 在新的治疗试验中的机制/目标参与。

Summary/Abstract There is growing evidence suggesting that the epigenetic processes such as histone acetylation may play a role in the alcohol-induced gene regulations and behavior. To date, the studies in animals demonstrated that histone deacetylases (HDACs), at least HDAC2 and HDAC3, could induce histone-related epigenetic changes after the treatment of ethanol. In addition, several studies have shown that HDAC inhibitors could be used to counter ethanol-induced behaviors and the ethanol-induced changes of HDAC levels. We have recently achieved a major research goal by developing a PET imaging agent, [11C]Martinostat that selectively binds to a subset of HDAC enzymes. [11C]Martinostat has been full characterized as a novel and the first PET radiotracer for epigenetic research through rodent imaging, non-human primates (NHPs) imaging and pilot healthy human imaging. We are extremely excited to take a large step forward in understanding epigenetic role in alcoholism by visualizing HDACs in the healthy and dysfunctional human brain in alcohol use disorder (AUD) patients. Together with the our multidisciplinary teams and strong collaborations, we are seeking the support through the R21/R33 mechanism for this high-risk, high-reward study to characterize the density and distribution of key HDACs throughout the brain of healthy subjects and in patients with alcoholism by applying our new PET imaging probe. Our initial data on [11C]Martinostat in humans strongly supports the success of our proposal for clinical imaging in healthy subjects (Aim 1) and in AUD patients (Aim 2 and Aim 3) in R21/R33 phases. 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 and facilitate proof of mechanism/target engagement in novel therapeutic trials.