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

总体汇总 拟议中心的首要目标是利用分子和电路生物标志物来推进生物技术的发展。 了解托吡酯治疗酒精使用障碍的机制及个体化治疗 患有创伤后应激障碍我们提出了一个整合的翻译重点改变兴奋和抑制 信号传导，重点是GABA和谷氨酸和相关电路，以模拟PTSD共病的神经生物学 和托吡酯的缓解作用我们将描述兴奋性和抑制性分子 利用脑和血浆中的基因组标记物， 啮齿类动物的标记在临床试验参与者中，我们将描述兴奋性和抑制性神经元信号传导 利用TMS诱发电位确定血浆标记物、GRIK1基因型和神经回路标记物 在脑电图，基于任务的功能性磁共振成像和磁共振波谱。 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来实现， 行政核心和科学咨询委员会（图1）。项目1由Silvia Fossati博士领导。 Jorge Manzanares Robles博士我们将研究两种剂量的 在单独的AUD、单独的PTSD和AUD+PTSD的动物模型中，托吡酯与赋形剂。在项目2中， Michael Bogenschutz医学博士和约书亚·李医学博士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名患有AUD和PTSD的受试者中的作用。在项目3中， Amit Etkin医学博士，博士查尔斯·R。Marmar医学博士我们将确定多模态成像标记，包括 基于任务的fMRI，EEG和MRS中的TMS诱发电位。成像标记物将用于表征 在患有AUD+PTSD的项目2临床试验参与者中的兴奋和抑制回路，以确定预测因素 和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 与项目1中相同或同源的血浆生物标志物相关。项目3的电路标记将 与项目1中相同或同源脑区的基因组标记相关。生物流体生物标志物 由Fossati博士领导的核心（BBC）将支持收集血浆生物标志物（GABA、谷氨酸、HPA轴， 神经肽、神经炎症和氧化应激），以及 项目2.分析和生物统计学核心（ABC）由尤金拉斯卡博士领导。Carole Segal博士 将支持实验设计、假设制定、功效计算和数据完整性， 管理和分析项目1，2和3，实施先进的统计模型， 预测项目1和项目2中对托吡酯的反应。

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.