1/3 Understanding PTSD through Postmortem Targeted Brain Multi-omics

1/3 通过死后靶向脑多组学了解 PTSD

基本信息

批准号：
10159964
负责人：
CHARLES B NEMEROFF
金额：
$ 60.05万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
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：
2018-07-25 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10159964
关键词：
Amygdaloid structure Anterior Area Arousal Autopsy Bioinformatics Biological Biological Markers Brain Brain Diseases Brain region Cell Nucleus Cells Chronic Chronic Post Traumatic Stress Disorder Clinical Collaborations Complex Coupled Critical Pathways DNA DNA Methylation Data Data Set Development Disease Disease model Epigenetic Process Exons Follow-Up Studies Fright Gene Expression Gene Proteins Genes Genetic Genetic Models Genetic Transcription Genomics Genotype Healthcare Systems Hippocampus (Brain)Hospitals Human Human Biology Individual Institutes Link Liquid Chromatography Major Depressive Disorder Measurement Medial Medical Mental disorders Methylation Modeling Molecular Molecular Biology Molecular Profiling Mood Disorders Morbidity - disease rate Multiomic Data Natural Disasters Negative Valence Neurobiology Outcome Pathologic Pathway interactions Patients Pattern Phenotype Pilot Projects Post-Traumatic Stress Disorders Prefrontal Cortex Prevalence Prospective Studies Proteins Proteome Proteomics Publications Publishing Quantitative Trait Loci RNA Regulation Research Domain Criteria Research Project Grants Resolution Risk Sampling Site Small RNA Statistical Models Survivors Symptoms Syndrome Terrorism Tissues Transcript Translating Trauma Universities Untranslated RNA Validation Vehicle crash War base brain tissue case control clinically significant cohort dentate gyrus diagnostic biomarker differential expression disorder risk epigenome epigenomics experience genetic variant genome wide association study genome-wide methylation pattern military trauma mind control mortality multiple omics neural circuit new therapeutic target novel novel therapeutics polygenic risk score predictive modeling protein expression psychobiologic psychologic relating to nervous system tandem mass spectrometry therapeutic target transcriptome transcriptome sequencing transcriptomics trauma exposure violent crime whole genome

项目摘要

Summary Post-traumatic Stress Disorder (PTSD) is among the most prevalent of psychiatric disorders. Trauma exposure is common, including natural disasters, terrorism, wars, automobile crashes, and violent crime. Although the majority of trauma victims experience the symptoms of re-experiencing, avoidance and hyperarousal, for the large majority of such individuals, these symptoms do not become chronic nor do they develop syndromal PTSD. It is critical to identify the underlying neurobiology of PTSD because of the very significant medical and psychiatric morbidity and mortality, and the promise of new therapeutics based on its biological underpinnings. Despite its clinical importance, there have yet to be human biology- focused postmortem studies of well-matched cases and controls to leverage the fact that this is arguably among the best understood Psychiatric Disorder in terms of neural circuit regulation. This proposal utilizes a Linked R01 mechanism across 3-sites (University of Miami (1), Lieber Institute for Brain Development (2), and McLean Hospital with Emory University (3)), to perform a postmortem, multi-omic study of brains from 300 total subjects: PTSD (civilian + military trauma, n=100), mood disorder non-PTSD psychiatric controls (n=100), and normal controls (n=100). We will focus on targeted brain regions with known differential association with PTSD risk as a function of identified intermediate phenotypes, including amygdala, prefrontal cortex and hippocampal dentate gyrus. We will determine differential DNA genotyping / methylation, RNA expression, and Proteomic patterns across brain areas. We hypothesize 1) that known pathways we have previously identified in the periphery and in PTSD models will be differentially identified in the brain regions of PTSD subjects, and 2) that genome- wide exploratory approaches will identify novel epigenetically gene pathways. Our main outcome will be a predictive model of genetic, epigenetic, transcriptomic, and proteomic profiles of brain regions from cases vs. controls. These data will allow an understanding of the region-specific genotype-dependent transcriptional and translational profiles, and findings will be integrated with detailed multi-omic data from other studies. We will use state-of-the-art statistical modeling, combined with rich biological and psychological phenotype measurements to determine a predictive model across conserved brain regions and molecular pathways. This novel, integrated, and impactful linked R01 proposal will lead to the identification of so far unknown trauma-associated genes and proteins, noncoding RNAs, and epigenetic marks in trauma related disorders and will allow the identification of novel therapeutic targets on the level of regulatory RNAs and proteins. Such a strategy has the potential to help redefine psychobiological subtypes of PTSD as well as to reduce the burden of chronic PTSD on our healthcare system.

概括创伤后应激障碍（PTSD）是最常见的精神疾病之一。创伤暴露很常见，包括自然灾害、恐怖主义、战争、车祸和暴力犯罪。尽管大多数创伤受害者都会经历重新经历、回避的症状和过度警觉，对于大多数此类个体来说，这些症状不会变成慢性的，也不会变成慢性的。他们会患上创伤后应激障碍综合症吗？确定 PTSD 的潜在神经生物学至关重要，因为非常重要的医学和精神疾病发病率和死亡率，以及新疗法的前景基于其生物学基础。尽管其临床重要性，但尚未在人类生物学中- 对匹配良好的病例和对照进行集中的事后研究，以利用这样一个事实：这可以说是就神经回路调节而言，这是最容易理解的精神疾病之一。该提案利用跨 3 个站点的 Linked R01 机制（迈阿密大学 (1)、利伯大脑发育研究所 (2) 和埃默里大学麦克莱恩医院 (3)），进行对 300 名受试者的大脑进行尸检、多组学研究：PTSD（平民+军事创伤，n=100），情绪障碍非 PTSD 精神病对照 (n=100) 和正常对照 (n=100)。我们将重点关注已知与 PTSD 风险存在差异关联的目标大脑区域作为已识别的函数中间表型，包括杏仁核、前额皮质和海马齿状回。我们将确定差异 DNA 基因分型/甲基化、RNA 表达和蛋白质组模式大脑区域。我们假设 1）我们之前在外围和内部发现的已知路径 PTSD 模型将在 PTSD 受试者的大脑区域中进行差异化识别，并且 2）基因组- 广泛的探索性方法将确定新的表观遗传基因途径。我们的主要成果将是病例大脑区域的遗传、表观遗传、转录组和蛋白质组谱的预测模型与控制。这些数据将有助于了解区域特异性基因型依赖性转录和翻译概况，研究结果将与详细的多组学数据相整合其他研究。我们将使用最先进的统计模型，结合丰富的生物学和心理学知识表型测量以确定跨保守大脑区域和分子的预测模型途径。这项新颖、综合且有影响力的 R01 提案将导致迄今为止的识别未知的创伤相关基因和蛋白质、非编码 RNA 以及创伤中的表观遗传标记相关疾病，并将允许在监管水平上识别新的治疗靶点 RNA 和蛋白质。这样的策略有可能帮助重新定义 PTSD 的心理生物学亚型以及减轻慢性创伤后应激障碍（PTSD）对我们医疗保健系统的负担。