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.

项目摘要/摘要 创伤后应激障碍(PTSD)是一种慢性、衰弱的精神障碍，发生在 创伤应激暴露后易感人群，患病率约为8%。当路径驱动时 创伤后应激障碍的治疗方法和分子图谱涉及多种生物系统，目前还没有 由于对疾病复杂性的不完全了解而建立的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 血液和死后大脑样本，因为获取活体人类创伤后应激障碍神经组织的机会有限。如果没有 尽管取得了重大突破，但创伤后应激障碍仍将是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(PTSD)中被广泛研究，因为它是PTSD的中枢 创伤应激的神经内分泌反应协调者。创伤后应激障碍的HPA轴失衡涉及低血压 低循环糖皮质激素水平引起的糖皮质激素信号转导，以及某些糖皮质激素的表观遗传失调 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的GC， 地塞米松(DEX)，模拟创伤后应激与IN相关的表观遗传和转录效应 体外和体内模型。然而，GC失调如何发展为创伤后应激障碍的机制尚不完全 缺乏未被发现的、基于GC的准确生物标志物和治疗方法。 阐明创伤后应激障碍的发病机制一直具有挑战性，但其他精神疾病的分子水平 诱导性多能干细胞(IPSC)模型已经成功地解释了病因，可能是由于 在控制遗传和外部刺激的同时，这些方法具有审问疾病的能力。到目前为止， 含有创伤后应激障碍病理的人类神经元(遗传学、表观遗传学和转录学)从未 在体外被审问。IPSC模型之外的最新进展--人类血液的转分化 通过直接重新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。作为一种 获得性疾病，越来越多的证据表明，从生活压力获得的表观遗传标记在创伤后应激障碍中所起的作用 发病机制，目前还没有在神经中捕获人类创伤后应激障碍表观遗传学的体外模式 组织，作为典型的诱导多能干细胞重新编程，重置表观遗传格局。令人兴奋的是， 有证据表明，直接重编程神经元(INS)可以保持其原始细胞的表观遗传特征。 该奖项的目标是开始模拟人类创伤后应激障碍的遗传学和表观遗传学。 基础和GC暴露条件下淋巴细胞分化为INS及其分子差异的研究 跨组。我们推测，识别甲基化和基因表达变化是由于GC活性 在创伤后应激障碍患者的淋巴细胞和INS之间共享将允许更好地区分和检测 创伤后应激障碍发病的关键途径。