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：
10237283
负责人：
Silvia Fossati
金额：
$ 8.59万
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 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10237283
关键词：
Administrative Personnel Aftercare Alcohols Amino Acids Amygdaloid structure Animal Model Animals Apoptosis Basic Science Biological Biological Assay Biological Markers Birds Blood Blood Volume Brain Brain region Brain-Derived Neurotrophic Factor Clinical Data Clinical Research Clinical Trials Collaborations Collection Control Animal Corticosterone Corticotropin-Releasing Hormone DNA DNA Methylation Data Data Analyses Data Collection Dose Electroencephalography Elements Enrollment Enzyme-Linked Immunosorbent Assay Equipment Fostering Functional Magnetic Resonance Imaging Future Gene Expression Gene Proteins Genomic DNA Genomics Genotype Glial Fibrillary Acidic Protein Guidelines Health Histology Human Human Resources Hydrocortisone IL6 gene Insula of Reil Intake Interdisciplinary Study Interleukin-10 Knowledge Laboratories Laboratory Personnel Modeling Motivation Mus Neurobiology Neurology Oxidative Stress Participant Pathway interactions Patients Placebos Plasma Post-Traumatic Stress Disorders Prediction of Response to Therapy Prefrontal Cortex Procedures Process Property Proteomics Psychiatry Public Health RNA Randomized Randomized Clinical Trials Research Research Personnel Research Subjects Research Support Resources Rewards Role Sampling Scheme Scientist Services Site Systems Biology TNF gene Testing Time Tissues Translational Research Treatment Efficacy Veterans Whole Blood alcohol comorbidity alcohol use disorder analog base biological adaptation to stress clinical research site clinical trial participant clinically relevant cohort comorbidity comparative cost effective cytochrome c design distributed data gamma-Aminobutyric Acid genomic RNA human subject hypothalamic-pituitary-adrenal axis metabolomics mitochondrial dysfunction molecular marker neurobiological mechanism neuroinflammation neuropeptide Y operation peptide hormone personalized medicine preclinical study programs protein expression response tool topiramate transcriptomics

项目摘要

Summary The Blood Biomarkers Core (BBC) is led by Dr. Silvia Fossati. For Project 1, blood and brain samples from all mice will be collected at sacrifice to quantify: 1) molecular biomarkers in animals subjected to all alcohol and/or PTSD-like models after treatment with two doses of topiramate (TPM) or vehicle to clarify the mechanisms of TPM action, and 2) biomarkers for the neurobiological comparison of animal models of alcohol+PTSD with PTSD-like animal models alone, alcohol models alone, naïve control animals, and resilient animals. For Project 2, blood will be collected from all enrolled randomized clinical trial (RCT) participants at 2 time points (before randomization and at week 12), and processed to determine molecular biomarkers, predictors of therapeutic efficacy and GRIK1 genotype, following best practices for blood biomarker analysis developed by our group at the NYU Cohen Veterans Center. Using Simoa and ELISA assays, we will determine the blood concentration of the following molecules: 1) excitatory and inhibitory amino acids altered in AUD, PTSD and PTSD+AUD and central to the hypothesized mechanisms of action of TPM (gluatamate and GABA); 2) peptides and hormones regulating responses of the hypothalamic–pituitary–adrenal (HPA) axis (corticotrophin releasing factor (CRF), corticosterone/cortisol, neuropeptide Y, and brain-derived neurotrophic factor (BDNF)); 3) biomarkers implicated in neuroinflammation (IL6, IL10, IL1α, TNFα, and glial fibrillary acidic protein); and 4) apoptosis, oxidative stress and mitochondrial dysfunction markers (cytochrome C). Integration across projects will be achieved by two design elements and three analytic strategies. Integrative Design Elements include: 1) mice subjected to alcohol and/or PTSD-like models in Project 1 will be stratified and randomized to topiramate/vehicle and PTSD+AUD clinical trial participants in Project 2 will be stratified and randomized to topiramate/placebo, creating parallel designs to advance discovery of mechanisms of topiramate action and predictors of treatment response; and 2) all blood biomarkers in mice in Project 1 will be ascertained in clinical trial participants for Project 2 (cortisol will replace corticosterone). Integrative Analytic Strategies include: 1) blood biomarkers levels after topiramate/placebo treatment in Project 2 will be related to plasma biomarkers levels in alcohol+PTSD models after topiramate/vehicle treatment in Project 1; 2) blood biomarker values obtained in clinical trial participants in Project 2 will be related to their Project 2 clinical data and to fMRI, TMS/EEG and MRS markers derived from Project 3; and 3) gene expression and protein expression markers ascertained in PFC, amygdala, cingulate, insula, VTA and accumbens in mice in Project 1 will be related to circuit markers obtained in the same brain regions in clinical trial participants in Project 3. Further, because we will be able to collect a higher blood volume in humans than mice, we will bank plasma, serum, whole blood, DNA, and RNA for future systems biology analyses, including genomics, transcriptomics, DNA methylation, metabolomics and proteomics.

概括血液生物标志物核心（BBC）由Silvia Fossati博士领导。对于项目1，来自所有人的血液和大脑样本将在牺牲时收集小鼠以量化：1）受所有酒精和/或受到所有酒精和/或的动物的分子生物标志物用两剂topramate（TPM）或车辆处理后的PTSD样模型，以阐明 TPM作用和2）生物标志物，用于与酒精+PTSD动物模型的神经生物学比较单独使用PTSD样动物模型，单独使用酒精模型，幼稚的对照动物和弹性动物。用于项目 2，将从2个时间点（之前随机化和第12周），并处理以确定分子生物标志物，这是治疗的预测指标效率和GRIK1基因型，遵循我们小组为血液生物标志物分析的最佳实践纽约大学科恩退伍军人中心。使用SIMOA和ELISA分析，我们将确定血液以下分子的浓度：1）AUD，PTSD改变的兴奋性和抑制性氨基酸 PTSD+AUD以及TPM（Gluatamate和GABA）作用机理的中心； 2）调节下丘脑 - 垂体 - 肾上腺（HPA）轴的肽和激素（皮质营养素）释放因子（CRF），皮质酮/皮质醇，神经肽Y和脑衍生的神经营养因子（BDNF））； 3）在神经炎症中实施的生物标志物（IL6，IL10，IL1α，TNFα和神经胶质原纤维酸性蛋白）；和4）凋亡，氧化应激和线粒体功能障碍标记（细胞色素C）。跨项目的集成将通过两个设计元素和三种分析策略来实现。集成设计元素包括： 1）在项目1中接受酒精和/或PTSD类模型的小鼠将被分层并随机分为项目2中的Topramate/Weart和PTSD+AUD临床试验参与者将被分层并随机分为托枕/安慰预测治疗反应的因素； 2）项目1小鼠中的所有血液标志物将在临床中确定项目2的试验参与者（皮质醇将取代皮质酮）。综合分析策略包括：1） topramate/安慰剂治疗项目2中的血液生物标志物水平将与血浆生物标志物有关在项目1中，托型/车辆治疗后酒精+PTSD模型的水平； 2）血液生物标志物值项目2中的临床试验参与者获得的将与他们的项目2临床数据和fMRI有关 TMS/EEG和MRS Markers来自项目3； 3）基因表达和蛋白质表达标记在PFC，Amygdala，cingulate，Insula，VTA和Accumbens在项目1中的确定将与项目3的临床试验参与者在同一大脑区域获得的电路标记。此外，我们与小鼠相比，将能够收集人类的血量更高，我们将库存等离子，血清，全血， DNA和RNA用于未来系统生物学分析，包括基因组学，转录组学，DNA甲基化，代谢组学和蛋白质组学。