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

项目概要/摘要 创伤后应激障碍（PTSD）是一种慢性的、使人衰弱的精神障碍， 创伤应激暴露后的易感个体，患病率约为8%。虽然路径驱动 方法和分子分析涉及创伤后应激障碍的多个生物系统， 由于对疾病复杂性的不完全理解， 机制等这种片面的理解受到我们依赖于人类研究PTSD的严重限制。 血液和死后的大脑样本，由于有限的访问活的人类创伤后应激障碍神经组织。没有 尽管创伤后应激障碍取得了重大突破，但它仍将是一个严重的公共卫生和社会经济负担。 下丘脑-垂体-肾上腺（HPA）轴在创伤后应激障碍中已被大量研究，因为它是中枢神经系统。 协调神经内分泌对创伤压力的反应。PTSD中HPA轴失衡涉及低水平 糖皮质激素（GC）信号传导由于低循环GC水平，和某些GC的表观遗传失调 相关基因已被证明是创伤后应激障碍的致病基因。各种研究已经利用了合成GC， 地塞米松（DEX），以模拟PTSD相关应激的表观遗传和转录效应， 体外和体内模型。然而，GC失调如何发展成PTSD的机制还不完全清楚。 目前还没有发现，缺乏准确的基于GC的生物标志物和治疗方法。 阐明PTSD的发病机制一直是一个挑战，但其他精神疾病的分子 诱导多能干细胞（iPSC）模型已经成功地阐明了病因，这可能是由于 这些方法在控制遗传学和外部刺激的同时询问疾病的能力。到目前为止， 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发现。 在试管中被审问。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PTSD的整体研究打开了大门。作为 获得性疾病，越来越多的证据表明，从生活压力中获得的表观遗传标记在创伤后应激障碍中起作用 发病机制，目前还没有在体外模式捕捉人类创伤后应激障碍表观遗传学的神经 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）可以保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创伤后应激障碍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iNs，并确定分子差异 跨群体。我们假设，确定甲基化和基因表达的变化，由于GC的活动， 在PTSD个体的淋巴细胞和iN之间共享，将允许更好地区分和检测 导致创伤后应激障碍发病的关键途径。

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.