Silvio O. Conte Center for Stress Peptide Advanced Research, Education, & Dissemination (SPARED) at McLean Hospital

Silvio O. Conte 应激肽高级研究、教育中心，

• 批准号: 10376397
• 负责人: William A. Carlezon
• 金额: $ 10.26万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10376397
• 关键词: Automobile Driving; Award; Biological Markers; Blood; Brain; Cells; Chronic; Complex; Computer Analysis; Data; Detection; Dexamethasone; Discrimination; Disease; Economic Burden; Education; Epigenetic Process; Etiology; Gene Expression; Genes; Genetic; Genetic Diseases; Genetic Models; Genetic Transcription; Glucocorticoids; Hospitals; Human; In Vitro; Individual; Life Stress; Lymphocyte; Mental disorders; Methylation; Modality; Modeling; Molecular; Molecular Profiling; Neurons; Neurosecretory Systems; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Peptides; Play; Population; Post-Traumatic Stress Disorders; Prevalence; Public Health; Research; Role; Sampling; Signal Transduction; Stimulus; Stress; Techniques; Time; Tissues; United States; base; biological systems; cost; effective therapy; experience; health economics; hypothalamic-pituitary-adrenal axis; in vivo Model; induced pluripotent stem cell; new therapeutic target; relating to nervous system; response; socioeconomics; stem cell biology; stem cell model; transcriptomics; transdifferentiation; traumatic stress

PROJECT SUMMARY/ABSTRACT Post-traumatic stress disorder (PTSD) is a chronic, debilitating, mental disorder that occurs in susceptible individuals after traumatic stress exposure, with a prevalence of ~8%. While pathway driven approaches and molecular profiling have implicated multiple biological systems in PTSD, there are no established biomarkers or effective treatments due to the incomplete understanding of the disorder’s complex mechanisms. This partial understanding is significantly restricted by our reliance on studying PTSD with human blood and post mortem brain samples, due to limited access to living human PTSD neural tissue. Without a significant breakthrough, PTSD will continue to be a severe public health and socio-economic burden. The hypothalamic-pituitary-adrenal (HPA) axis has been much studied in PTSD since it is the central coordinator of the neuroendocrine response to traumatic stress. HPA-axis imbalance in PTSD involves low glucocorticoid (GC) signaling due to low circulating GC levels, and epigenetic dysregulation of certain GC related genes has been shown to be pathogenic for PTSD. Various studies have utilized the synthetic GC, dexamethasone (DEX), to model the epigenetic and transcriptional effects of PTSD associated stress with in vitro and in vivo models. Yet, the mechanisms for how GC dysregulation develops into PTSD are not fully uncovered, and accurate GC-based biomarkers and treatments are lacking. Elucidating the pathogenesis of PTSD has been challenging, but other psychiatric disorders’ molecular etiologies have been successfully illuminated with induced pluripotent stem cell (iPSC) modeling, possibly due to the approaches’ capacity to interrogate diseases while controlling for genetics and external stimuli. To date, human neurons containing PTSD pathology (genetics, epigenetics, and transcriptomics) have never been interrogated in vitro. A recent advancement beyond iPSC modeling, transdifferentiation of human blood lymphocytes into neurons via direct reprogramming, opens the door for PTSD to be studied holistically. As an acquired disease, evidence is growing about the role epigenetic marks acquired from life stress plays in PTSD pathogenesis, and there is currently no in vitro modality for capturing human PTSD epigenetics in neural tissue, as typical induced pluripotent stem cell reprogramming resets the epigenetic landscape. Excitingly, evidence suggests directly reprogrammed neurons (iNs) can maintain their original cell’s epigenetic signatures. The objective for this award is to begin to model the genetics and epigenetics of PTSD in human lymphocytes differentiated to iNs in basal and GC-exposed conditions and determine molecular differences across groups. We postulate that identifying methylation and gene expression changes due to GC activity that are shared across lymphocytes and iNs in PTSD individuals will allow for better discrimination and detection of the key pathways driving PTSD pathogenesis.

项目概要/摘要 创伤后应激障碍 (PTSD) 是一种慢性、使人衰弱的精神障碍，发生在 遭受创伤应激后易感人群，患病率约为 8%。当路径驱动时 方法和分子分析表明 PTSD 涉及多个生物系统，但目前还没有 由于对疾病复杂性的不完全了解，已建立生物标志物或有效的治疗方法 机制。这种片面的理解受到我们对人类创伤后应激障碍研究的依赖的严重限制。 由于活体人类 PTSD 神经组织的获取有限，因此无法获取血液和死后脑样本。没有一个 尽管取得了重大突破，但创伤后应激障碍将继续成为严重的公共卫生和社会经济负担。 下丘脑-垂体-肾上腺 (HPA) 轴在 PTSD 中得到了大量研究，因为它是中枢神经系统。 神经内分泌对创伤应激反应的协调者。 PTSD 中的 HPA 轴失衡涉及低 由于循环 GC 水平低以及某些 GC 的表观遗传失调而导致的糖皮质激素 (GC) 信号转导 相关基因已被证明对 PTSD 具有致病性。各种研究都利用了合成气相色谱， 地塞米松 (DEX)，用于模拟 PTSD 相关压力的表观遗传和转录效应 体外和体内模型。然而，GC 失调如何发展为 PTSD 的机制尚不完全清楚。 尚未发现，并且缺乏基于 GC 的准确生物标志物和治疗方法。 阐明 PTSD 的发病机制一直具有挑战性，但其他精神疾病的分子机制 诱导多能干细胞 (iPSC) 模型已成功阐明病因，可能是由于 这些方法在控制遗传和外部刺激的同时询问疾病的能力。迄今为止， 含有 PTSD 病理学（遗传学、表观遗传学和转录组学）的人类神经元从未被研究过。 在体外进行询问。 iPSC 建模之外的最新进展，人类血液的转分化 通过直接重编程将淋巴细胞转化为神经元，为全面研究创伤后应激障碍打开了大门。作为一个 越来越多的证据表明，生活压力获得的表观遗传标记在 PTSD 中发挥着作用 发病机制，目前还没有体外方法来捕捉人类 PTSD 表观遗传学的神经 组织，因为典型的诱导多能干细胞重编程重置了表观遗传景观。令人兴奋的是， 有证据表明，直接重编程的神经元（iN）可以维持其原始细胞的表观遗传特征。 该奖项的目的是开始模拟人类 PTSD 的遗传学和表观遗传学 淋巴细胞在基础和 GC 暴露条件下分化为 iN，并确定分子差异 跨群体。我们假设，识别由于 GC 活性而导致的甲基化和基因表达变化 PTSD 个体的淋巴细胞和 iN 之间共享，这将有助于更好地区分和检测 驱动 PTSD 发病机制的关键途径。