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

总体摘要 拟议中心的首要目标是利用分子和回路生物标记物来推动 托吡酯治疗酒精使用障碍的机制及个体化治疗的认识 与创伤后应激障碍并存。我们建议对兴奋性和抑制性的变化进行综合翻译。 以GABA和谷氨酸及相关回路为重点的信号转导，以模拟创伤后应激障碍的神经生物学 与创伤后应激障碍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研究AUD与创伤后应激障碍共病动物模型中的标记 啮齿动物身上的标记。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的特征 利用TMS诱发电位确定血浆标志物、GRIK-1基因和神经回路标志物 在EEG中，基于任务的功能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由西尔维娅·福萨蒂博士领导。 和豪尔赫·曼萨纳雷斯·罗伯斯博士，我们将研究两种剂量的 托吡酯与赋形剂在单纯创伤后应激障碍、单纯创伤后应激障碍和创伤后应激障碍+创伤后应激障碍动物模型中的比较。在项目2中，领头人 Michael Bogenschutz医学博士和Joshua Lee医学博士我们将研究行为、遗传和血浆生物标记物 托吡酯与安慰剂在150名同时患有AUD和PTSD的参与者中的作用。在项目3中，由 Amit Etkin医学博士和Charles R.Marmar医学博士，我们将确定多模式成像标记，包括 将使用基于任务的fMRI、EEG中的TMS诱发电位和MRS成像标记来表征 AUD+PTSD患者在项目2临床试验参与者中的兴奋和抑制回路以确定预测因素 以及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记物有关。项目3中的电路标记物将 与项目1中相同或同源脑区的基因组标记相关：生物体液生物标记 由福萨蒂博士领导的核心(BBC)将支持血浆生物标记物(GABA、谷氨酸、HPA轴、 神经肽、神经炎性和氧化应激)在项目1和临床试验参与者中 项目2.由尤金·拉斯卡博士和卡罗尔·西格尔博士领导的分析和生物统计学核心(ABC)。 将支持实验设计、假设的形成、功率计算和数据完整性， 对项目1、2、3进行管理和分析，实施先进的个性化统计模型 项目1和项目2中托吡酯的疗效预测。

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.