Leveraging biomarkers for personalized treatment of alcohol use disorder comorbid with PTSD

利用生物标志物对合并 PTSD 的酒精使用障碍进行个性化治疗

基本信息

批准号：
10473674
负责人：
Charles R. Marmar
金额：
$ 120.49万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-20 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10473674
关键词：
Affect Aftercare Alcohols Animal Model Animals Behavior Behavioral Behavioral Genetics Biological Biological Markers Biostatistics Core Blood Brain Brain region Clinical Clinical Treatment Clinical Trials Cognition Cognitive Collection Complement Data Analytics Disease model Doctor of Medicine Doctor of Philosophy Dose Electroencephalography Elements Emotional Emotions Equilibrium Evoked Potentials Experimental Designs Formulation Fostering Freezing Functional Magnetic Resonance Imaging Gene Expression Genetic Genotype Glutamates Goals Human Impairment Individual Interdisciplinary Study Investigation Lead Link Machine Learning Magnetic Resonance Spectroscopy Measures Mediating Mediation Mission Modeling Molecular Multimodal Imaging National Institute on Alcohol Abuse and Alcoholism Neurobiology Neurocognitive Neurons Neuropeptides Outcome Oxidative Stress Participant Patients Pharmacology Placebos Plasma Post-Traumatic Stress Disorders Prediction of Response to Therapy Randomized Randomized Clinical Trials Regulation Research Research Project Grants Resources Rodent Signal Transduction Statistical Data Interpretation Statistical Models Stimulus Structure Symptoms Testing Transcranial magnetic stimulation Translations Treatment outcome Work alcohol abuse therapy alcohol comorbidity alcohol cue alcohol use disorder base behavioral study clinical imaging clinical trial participant clinically relevant cognitive neuroscience comorbidity data integrity data management design drinking dual diagnosis effective therapy emotion regulation executive function gamma-Aminobutyric Acid genomic biomarker hypothalamic-pituitary-adrenal axis imaging biomarker imaging study molecular marker mortality mouse model multimodality neural circuit neurobiological mechanism neuroinflammation neurophysiology neurotransmission personalized medicine personalized predictions pre-clinical precision medicine predicting response predictive modeling protein expression response source localization topiramate treatment comparison treatment effect treatment response

项目摘要

Overall Summary The overarching goal of the proposed center is to leverage molecular and circuit biomarkers to advance the understanding of mechanisms and personalized treatment of topiramate treatment of Alcohol Use Disorder comorbid with PTSD. We propose an integrative translational focus on alterations in excitatory and inhibitory signaling, focusing on GABA and glutamate and related circuitry, to model the neurobiology of PTSD comorbid with PTSD and the mitigating effects of topiramate. We will characterize excitatory and inhibitory molecular markers in an animal model of AUD comorbid with PTSD, utilizing genomic markers in the brain and plasma markers in rodents. In clinical trial participants we will characterize excitatory and inhibitory neuronal signaling by ascertaining plasma markers, GRIK 1 genotype and neural circuit markers utilizing TMS evoked potentials in EEG, task-based functional MRI and MR spectroscopy. This goal will be achieved through the activities of three research projects supported by two research cores, the administrative core and the Scientific Advisory Board (Figure1). In Project 1 lead by Silvia Fossati Ph.D. and Jorge Manzanares Robles Ph.D. we will study the behavioral and molecular effects of two doses of topiramate vs. vehicle in animal models of AUD alone, PTSD alone and AUD+PTSD. In Project 2 lead by Michael Bogenschutz M.D. and Joshua Lee M.D. we will study the behavioral, genetic and plasma biomarker effects of topiramate vs. placebo in 150 participants with co-occurring AUD and PTSD. In project 3 lead by Amit Etkin M.D., Ph.D. and Charles R. Marmar M.D. we will ascertain multi-modal imaging markers including task based fMRI, TMS evoked potentials in EEG and MRS. Imaging markers will be used to characterize excitatory and inhibitory circuits in Project 2 clinical trial participants with AUD+PTSD to determine predictors and mechanisms of topiramate vs. placebo treatment outcomes. Plasma biomarkers in Project 2 will be related to the same or homologous plasma biomarkers in Project 1. Circuit markers from Project 3 will be related to genomic markers in the same or homologous brain regions in Project 1. The Biofluids Biomarker Core (BBC) lead by Dr. Fossati will support collection of plasma biomarkers (GABA, glutamate, HPA axis, neuropeptides, neuroinflammatory and oxidative stress) in animals in Project 1 and clinical trial participants in Project 2. The Analytics and Biostatistics Core (ABC) lead by Eugene Laska Ph.D. and Carole Segal Ph.D. will support experimental design, formulation of hypothesis, power calculations, and data integrity, management and analysis for Project 1, 2 and 3, implementing advanced statistical models for individualized prediction of response to topiramate in Project 1 and Project 2.

总结拟议中心的总体目标是利用分子和电路生物标志物来推进了解机制和对托吡酯治疗酒精疾病的个性化治疗与PTSD合并。我们建议对兴奋性和抑制性改变的综合翻译重点信号传导，专注于GABA和谷氨酸以及相关电路，以建模PTSD合并症的神经生物学具有PTSD和托吡酯的缓解作用。我们将表征兴奋性和抑制性分子使用PTSD的AUD合并动物模型中的标记，利用大脑和等离子体中的基因组标记啮齿动物中的标记。在临床试验参与者中，我们将表征兴奋性和抑制性神经元信号传导通过确定血浆标记，Grik 1基因型和使用TMS的神经回路标记物诱发电位在EEG中，基于任务的功能MRI和MR光谱学。这一目标将通过由两个研究核心支持的三个研究项目的活动实现行政核心和科学顾问委员会（图1）。在项目1中，Silvia Fossati博士领导。和豪尔赫·曼萨纳雷斯·罗伯斯（Jorge Manzanares Robles）博士我们将研究两种剂量的行为和分子效应单独使用AUD，PTSD和AUD+PTSD的动物模型中的托吡酯与车辆。在项目2中领导 Michael Bogenschutz M.D.和Joshua Lee M.D.我们将研究行为，遗传和血浆生物标志物托吡酯与安慰剂在150名参与者中的影响。在项目3中领导 Amit Etkin M.D.，博士和Charles R. Marmar M.D.我们将确定包括基于任务的fMRI，TMS诱发了脑电图和MRS的潜力。成像标记将用于表征 Project 2临床试验参与者的兴奋性和抑制回路，以确定预测因子托吡酯与安慰剂治疗结果的机制。项目2中的血浆生物标志物将是项目1中的相同或同源等离子体生物标志物有关。项目3的电路标记将是与项目1中相同或同源大脑区域中的基因组标记有关。生物体生物标志物 Fossati博士领导的Core（BBC）将支持等离子生物标志物（GABA，谷氨酸，HPA轴，在项目1的动物和临床试验参与者中，神经肽，神经炎症和氧化应激）项目2。尤金·拉斯卡（Eugene Laska）博士领导的分析和生物统计学核心（ABC）。和Carole Segal博士将支持实验设计，假设的制定，功率计算和数据完整性，项目1、2和3的管理和分析，为个性化实施高级统计模型项目1和项目2中对托吡酯的反应预测。