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

基本信息

批准号：
9751682
负责人：
Changning Wang
金额：
$ 59.22万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751682
关键词：
Adult Aftercare Age Alcohol consumption Alcoholism Alcohols Amygdaloid structure Animal Model Animals Anxiety Applications Grants Behavior Binding Brain Brain Diseases Brain region Cell Line Chromatin 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 Histone Deacetylase Inhibitor Histones Human Image Individual Institutional Review Boards Investigation Location MS-275 Magnetic Resonance Magnetic Resonance Imaging Maps Measures Motivation Neurobiology Neurons Patient imaging Patients Phase Phased Innovation Awards Pilot Projects Play Positron-Emission Tomography Prefrontal Cortex Protein Isoforms Protocols documentation Rattus Reporting Research Rodent Role Sex Functioning Sodium Butyrate Substance abuse problem Testing Therapeutic Trials Tissue Sample Trichostatin A alcohol behavior alcohol measurement alcohol use disorder base clinical imaging density deter alcohol use effective therapy first-in-human high reward high risk human imaging human old age (65+)imaging agent imaging probe imaging study in vivo insight male multidisciplinary non-invasive imaging nonhuman primate novel novel therapeutics radiotracer sex success therapeutic target

项目摘要

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.

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发挥着重要作用。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脱乙酰酶 (HDAC)，至少是 HDAC2 和 HDAC3，可以诱导组蛋白相关的表观遗传变化经过乙醇处理后。此外，多项研究表明，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 实现了一个主要研究目标选择性结合 HDAC 酶的子集。 [11C]Martinostat 已被充分描述为一种新型且第一个通过啮齿动物成像、非人类灵长类动物 (NHP) 成像进行表观遗传学研究的 PET 放射性示踪剂并试点健康人体成像。我们非常高兴能够在理解方面向前迈出一大步通过观察酒精使用过程中健康和功能失调的人脑中的 HDAC 来观察酒精中毒中的表观遗传作用障碍（AUD）患者。与我们的多学科团队和强有力的合作一起，我们正在通过以下方式寻求支持这项高风险、高回报研究的 R21/R33 机制来表征关键的密度和分布通过应用我们的新 PET，健康受试者和酗酒患者大脑中的 HDAC 成像探头。我们关于人类 [11C]Martinostat 的初步数据有力地支持了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 成像人类使用 [11C]Martinostat 将为有关染色质修饰的基本问题提供答案以一种迄今为止不可能的方式研究活人大脑中的酶，并有助于证明新颖治疗试验中的机制/目标参与。