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Site 3/3, Understanding PTSD through Postmortem Targeted Brain Multiomics

站点 3/3，通过死后目标脑多组学了解 PTSD

基本信息

批准号：
10159979
负责人：
KERRY J. RESSLER
金额：
$ 60.3万
依托单位：
MCLEAN HOSPITAL
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/10159979
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.

总结创伤后应激障碍（PTSD）是最常见的精神疾病之一。创伤暴露是常见的，包括自然灾害、恐怖主义、战争、车祸和暴力。犯罪虽然大多数创伤受害者的经验的症状，重新体验，避免对于大多数这样的人来说，这些症状不会变成慢性的，他们是否会患上创伤后应激障碍综合征识别PTSD的潜在神经生物学是至关重要的，非常显著的医疗和精神病发病率和死亡率，以及新疗法的前景基于其生物学基础。尽管它在临床上很重要，但还没有人类生物学- 对匹配良好的病例和对照进行集中的事后研究，以利用这一事实，在神经回路调节方面是最好理解的精神疾病之一。该提案利用了跨3个站点的链接R 01机制（迈阿密大学（1），Lieber 脑发育研究所（2）和埃默里大学姆克林医院（3）），执行一项对来自300名受试者的脑的死后多组学研究：PTSD（平民+军事创伤，n=100），心境障碍非PTSD精神对照组（n=100）和正常对照组（n=100）。我们将专注于与PTSD风险具有已知差异关联的靶向脑区域，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表达和蛋白质组学模式，大脑区域我们假设：1）我们以前在外周和外周血中发现的已知通路，创伤后应激障碍模型将在创伤后应激障碍受试者的大脑区域中进行差异鉴定，2）该基因组- 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来自病例的脑区域的遗传、表观遗传、转录组学和蛋白质组学谱的预测模型 vs.对照这些数据将使我们能够了解特定区域的基因型依赖性转录和翻译谱，以及研究结果将与详细的多组学数据整合，其他研究。我们将使用最先进的统计建模，结合丰富的生物和心理表型测量以确定跨保守脑区域和分子的预测模型途径。这一新颖、集成且有影响力的关联R 01提案将导致识别到目前为止创伤中未知的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，并将允许在调节水平上鉴定新的治疗靶点。 RNA和蛋白质。这种策略有可能帮助重新定义创伤后应激障碍的心理生物学亚型以及减轻慢性创伤后应激障碍对我们医疗系统的负担。