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：
9924647
负责人：
CHARLES B NEMEROFF
金额：
$ 59.91万
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/9924647
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 Military Personnel 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 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

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 Military Personnel 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 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

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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）是最普遍的精神疾病之一。创伤暴露很常见，包括自然灾害，恐怖主义，战争，汽车坠毁和暴力犯罪。尽管大多数创伤受害者经历了重新体验的症状，但避免对于大多数此类人来说，这些症状并没有变得慢性或它们会发展综合症PTSD吗？确定PTSD的潜在神经生物学至关重要非常重要的医学和精神病发病率和死亡率，以及新治疗学的希望基于其生物基础。尽管其临床重要性，但尚未有人类生物学 - 匹配案例和对照的重点验尸研究，以利用这一事实可以说是这样的事实在神经回路调节方面，最好理解的精神障碍。该提案利用了3点跨的链接R01机制（迈阿密大学（1），lieber 大脑发展研究所（2）和埃默里大学（Emory University）的麦克莱恩（McLean）医院（3））验尸，来自300名受试者的大脑的多摩变研究：PTSD（民用 +军事创伤，n = 100），情绪障碍非PTSD精神病控制（n = 100）和正常对照（n = 100）。我们将重点关注靶向大脑区域已知与PTSD风险的差异关联是确定的函数中间表型，包括杏仁核，前额叶皮层和海马齿状回。我们将确定跨差异DNA基因分型 /甲基化，RNA表达和蛋白质组学跨的蛋白质组学模式大脑区域。我们假设1）我们以前在外围和中已经鉴定过的已知途径 PTSD模型将在PTSD受试者的大脑区域差异化，2）基因组 - 广泛的探索方法将确定新型的表观遗传基因途径。我们的主要结果将是从病例的遗传，表观遗传学，转录组和蛋白质组学特征的预测模型与控件。这些数据将允许了解依赖区域的基因型转录和翻译配置文件，调查结果将与来自其他研究。我们将使用最先进的统计建模，并结合丰富的生物学和心理学表型测量以确定跨保守大脑区域和分子的预测模型途径。这部小说，综合和有影响力的链接R01提案将导致到目前为止的识别创伤相关基因和蛋白质，非编码RNA和表观遗传标记相关疾病，将允许在调节水平上鉴定新的治疗靶标 RNA和蛋白质。这种策略有可能帮助重新定义PTSD的心理生物学亚型以及减轻我们医疗保健系统中慢性PTSD的负担。