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：
10473677
负责人：
Silvia Fossati
金额：
$ 9.36万
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/10473677
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，项目 1 的血液和脑样本来自所有患者。将在处死时收集小鼠以量化：1）遭受所有酒精和/或使用两剂托吡酯 (TPM) 或媒介物治疗后的 PTSD 样模型，以阐明其机制 TPM 作用，以及 2) 用于酒精+PTSD 动物模型神经生物学比较的生物标志物单独的 PTSD 类动物模型、单独的酒精模型、幼稚对照动物和有弹性的动物。 2、将在2个时间点（之前）从所有入组的随机临床试验（RCT）参与者中采集血液随机化和第 12 周），并进行处理以确定分子生物标志物、治疗的预测因子功效和 GRIK1 基因型，遵循我们小组开发的血液生物标志物分析最佳实践纽约大学科恩退伍军人中心使用 Simoa 和 ELISA 检测，我们将测定血液。以下分子的浓度：1) AUD、PTSD 中兴奋性和抑制性氨基酸的改变和 PTSD+AUD，对于 TPM 的促进作用机制至关重要（谷氨酸和 GABA 2)；调节下丘脑-垂体-肾上腺 (HPA) 轴反应的肽和激素（促肾上腺皮质激素释放因子（CRF）、皮质酮/皮质醇、神经肽Y和脑源性神经营养因子（BDNF）； 3) 与神经炎症有关的生物标志物（IL6、IL10、IL1α、TNFα 和胶质纤维酸性蛋白）；4) 细胞凋亡、氧化应激和线粒体功能障碍标记物（细胞色素 C）。将通过两个设计元素和三个分析策略来实现，其中包括： 1) 项目 1 中接受酒精和/或 PTSD 样模型的小鼠将被分层并随机分组项目 2 中的托吡酯/载体和 PTSD+AUD 临床试验参与者将被分层和随机分配托吡酯/安慰剂，创建并行设计以推进托吡酯作用机制的发现和治疗反应的预测因子；2) 项目 1 中小鼠的所有血液生物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）包括：1)。项目2中托吡酯/安慰剂治疗后的血液生物标志物水平将与血浆生物标志物相关项目 1) 中托吡酯/媒介物治疗后酒精+PTSD 模型的水平；血液生物标志物值项目 2 的临床试验参与者获得的数据将与其项目 2 的临床数据和功能磁共振成像相关，来自项目3的TMS/EEG和MRS标记；以及3)基因表达和蛋白质表达标记项目 1 中在小鼠 PFC、杏仁核、扣带皮层、岛叶、VTA 和伏隔核中确定的结果将与在项目 3 的临床试验参与者的相同大脑区域中获得的电路标记。此外，因为我们将能够在人类中收集比小鼠更多的血量，我们将储存血浆、血清、全血，用于未来系统生物学分析的 DNA 和 RNA，包括基因组学、转录组学、DNA 甲基化、代谢组学和蛋白质组学。