2/3 Understanding PTSD through Postmortem Targeted Brain Multi-omics

摘要 创伤后应激障碍(PTSD)是最常见的精神障碍之一。 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经历了重新经历、回避的症状 和过度觉醒，对于大多数这样的人来说，这些症状不会变成慢性的，也不会 他们会患上综合征性创伤后应激障碍吗。确定创伤后应激障碍的潜在神经生物学至关重要，因为 非常重要的医疗和精神疾病发病率和死亡率，以及新疗法的前景 基于它的生物学基础。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重点尸检研究，以利用这一事实，即这是有争议的 在神经回路调节方面，最被理解的精神障碍之一。 该提案在3个站点之间使用链接的R01机制(迈阿密大学(1)，利伯 脑发育研究所(2)和埃默里大学麦克莱恩医院(3)) 对300名受试者的死后大脑进行多组学研究：创伤后应激障碍(平民军事创伤，n=100)， 心境障碍非创伤后应激障碍精神病组(n=100)和正常对照组(n=100)。我们将重点关注 已知与创伤后应激障碍风险存在差异关联的目标脑区 中间表型，包括杏仁核、前额叶皮质和海马齿状回。我们会 确定不同的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 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进行区分，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 病例脑区遗传、表观遗传、转录和蛋白质组学特征的预测模型 与控制的对比。这些数据将使我们能够了解特定地区的基因依赖 转录和翻译概况，以及发现将与详细的多组数据相结合 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 表型测量确定跨保守脑区和分子的预测模型 小路。这一新颖、集成和有影响力的R01提案将导致迄今 创伤中未知的创伤相关基因和蛋白、非编码RNA和表观遗传标记 并将允许在调节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给我们的医疗系统带来的负担。

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.