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

通过非侵入性 PET 成像量化酒精使用障碍的表观遗传机制

• 批准号: 9168787
• 负责人: Changning Wang
• 金额: $ 27.8万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9168787
• 关键词: Adult; Aftercare; Age; Alcohol consumption; Alcoholism; Alcohols; Amygdaloid structure; Animal Model; Animals; Anxiety; Applications Grants; Behavior; Binding; Brain; Brain region; Cell Line; Chromatin; Clinical; Collaborations; Data; Development; Enzymes; Epigenetic Process; Ethanol; FDA approved; Female; Functional disorder; Funding; Gene Expression Regulation; Goals; HDAC2 gene; HDAC3 gene; Health; Histone Acetylation; Histone Deacetylase; Histones; Human; Image; Individual; Institutional Review Boards; Investigation; Life; Location; MS-275; Magnetic Resonance; Magnetic Resonance Imaging; Maps; Measurement; Measures; Motivation; Neurobiology; Neurons; Patients; Phase; Phased Innovation Awards; Pilot Projects; Play; Positron-Emission Tomography; Prefrontal Cortex; Prevention; Protein Isoforms; Protocols documentation; Rattus; Reporting; Research; Rodent; Role; Sex Functioning; Sodium Butyrate; Substance abuse problem; Testing; Therapeutic Trials; Tissue Sample; Trichostatin A; abstracting; alcohol behavior; alcohol use disorder; base; density; effective therapy; high reward; high risk; human old age (65+); imaging agent; imaging probe; in vivo; inhibitor/antagonist; insight; male; man; multidisciplinary; non-invasive imaging; nonhuman primate; novel; novel therapeutics; radiotracer; sex; success; therapeutic target

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.

总结/摘要 越来越多的证据表明，表观遗传过程，如组蛋白乙酰化，可能发挥了重要作用。 在酒精诱导的基因调控和行为中的作用。迄今为止，动物研究表明， 组蛋白去乙酰化酶（HDAC），至少是HDAC 2和HDAC 3，可以诱导组蛋白相关的表观遗传学改变 乙醇处理后。此外，一些研究表明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PET成像剂[11 C]Martinostat实现了一个主要的研究目标， 选择性地结合HDAC酶的子集。[11 C]Martinostat被充分描述为一种新颖的， 第一个PET放射性示踪剂通过啮齿动物成像，非人类灵长类动物（NHP）成像进行表观遗传学研究 并进行健康人体成像。我们非常兴奋地向前迈出了一大步， 通过观察酒精使用中健康和功能障碍的人脑中的HDAC， 疾病（AUD）患者。 与我们的多学科团队和强大的合作一起，我们正在寻求支持， R21/R33机制，这种高风险，高回报的研究，以表征密度和分布的关键 通过应用我们的新PET，在健康受试者和酒精中毒患者的大脑中观察HDAC 成像探头 我们关于[11 C]Martinostat在人体中的初步数据强烈支持我们临床成像提案的成功 在R21/R33阶段的健康受试者（目标1）和AUD患者（目标2和目标3）中。PET-MR成像在 使用[11 C]Martinostat的人类将为染色质修饰的基本问题提供答案 酶在活的人类大脑中以一种直到现在还不可能的方式， 新的治疗试验中的机制/靶点参与。