Deciphering Biological Linkages Between PTSD and Respiratory Disease in WTC Respo

描述（由申请人提供）：2001年9月11日发生在世界旅游中心的恐怖袭击是一场非同寻常的环境灾难，给救援和恢复工作人员带来了前所未有的身心创伤。因此，十多年后，下呼吸道症状（LRS）和创伤后应激障碍（PTSD）仍然是世界贸易中心（WTC）灾难的标志性后遗症，多达60%的响应者在十年后出现临床显著症状。我们的研究项目由niosh资助，重点是了解WTC应答者中这种共病的程度和影响及其潜在机制，以确定更有效的诊断生物标志物和治疗干预措施。我们目前的建议是基于我们正在进行的流行病学研究的结果（NIOSH奖200- 2011-39410），我们发现WTC-Health Program （HP）应答者的PTSD与LRS横断面相关（Luft et al. 2012），并且与2.5年后新发LRS增加两倍相关（Kotov et al.，提交）。这些发现对PTSD/LRS关系的潜在机制提出了重要的问题。为了揭示其机制，我们首先确认了Uddin等人（2010）报道的表观遗传变异（NIOSH奖U01OH010416）。在237名应答者（最终目标N=500）的初始样本中，我们发现四个免疫基因（DAB2IP、TAOK3、TLR9、TRAF3）在PTSD应答者中甲基化程度较低。这些基因调节NF - B的活性，NF - B是一种转录因子，是促炎基因表达的中心调节因子，与多种炎症性疾病和癌症密切相关。它们在外周血白细胞（免疫细胞）中高度表达，是炎症和免疫反应的组成部分。这些基因的去甲基化也与LRS有关。我们现在有能力利用我们之前NIOSH资助的研究，在提议的两年时间框架内实现以下具体目标：1)在有和没有创伤后应激障碍的应答者中确定淋巴细胞和单核细胞免疫细胞群体中的差异DNA甲基化模式。我们将确定特定的WTC暴露、PTSD症状、共病精神疾病和特定呼吸系统疾病是否与这些表观遗传差异有关。2)将PTSD相关甲基化模式与血浆中细胞特异性基因表达和细胞因子水平联系起来，以确定表观遗传差异的下游影响。3)在获得生物样本2年后评估参与者的健康结果，以确定甲基化、基因表达和炎症细胞因子水平是否与LRS的发生和持续有关。我们还将纵向检验这些生物学机制是否介导PTSD- LRS关系。这项提议的研究将首次检查导致PTSD和LRS共病的机制，这是一个非常普遍的问题，尽管采用了常规治疗方法，但仍然存在。阐明连接这两种疾病的病因途径将有助于确定生物标志物，这些标志物可能对诊断有用，并针对PTSD中发生改变的特定细胞、细胞因子或基因进行更具体、更有效的治疗。本研究还将通过阐明有毒灾难对人类生物学的影响来促进科学，因此其结果将与其他受影响人口有关，其中许多人承受着类似的负担。

DESCRIPTION (provided by applicant): The September 11, 2001, terrorist attack on the World Travel Center was an extraordinary environmental disaster resulting in an unprecedented combination of physical and emotional trauma to the rescue and recovery workers. As a result, over a decade later, lower respiratory symptoms (LRS) and post-traumatic stress disorder (PTSD) continue to be the signature sequelae of the World Trade Center (WTC) disaster, with as many as 60% of responders experiencing clinically significant symptoms a decade later. Our NIOSH-funded program of research is focused on the understanding the magnitude and impact of this comorbidity in WTC responders and its underlying mechanisms in order to identify more effective diagnostic biomarkers and therapeutic interventions. Our current proposal is informed by results of our ongoing epidemiologic study (NIOSH award 200- 2011-39410), where we found that PTSD is associated with LRS in WTC-Health Program (HP) responders cross-sectionally (Luft et al. 2012) and is associated with a two-fold increase in new-onset LRS 2.5 years later (Kotov et al., submitted. These findings raise important questions about mechanisms underlying the PTSD/LRS relationship. In an effort to uncover the mechanisms, we began by confirming epigenetic variations reported by Uddin et al. (2010) (NIOSH award U01OH010416). In our initial sample of 237 responders (final target N=500), we found four immune genes (DAB2IP, TAOK3, TLR9, TRAF3) to be less methylated in responders with PTSD. These genes regulate activity of NF¿B, a transcription factor that is a central regulator of pro-inflammatory gene expression and strongly linked to a variety of inflammatory diseases and cancers. They are highly expressed in peripheral blood leukocytes (immune cells) and integral to inflammation and immune responses. De-methylation in these genes was also associated with LRS. We are now well-positioned to leverage our prior NIOSH funded research to accomplish the following specific aims within the proposed two-year timeframe: 1) Identify differential DNA methylation patterns within the lymphocytic and monocyte immune cell population in responders with and without PTSD. We will determine whether specific WTC exposures, PTSD symptoms, comorbid psychiatric conditions, and specific respiratory disorders are associated with these epigenetic differences. 2) Relate methylation patterns associated with PTSD to cell-specific gene expression and cytokine levels in plasma to determine downstream effects of epigenetic differences. 3) Assess health outcomes of participants 2 years after the biological samples were obtained to determine whether methylation, gene expression, and levels of inflammatory cytokines contribute to onset and persistence of LRS. We also will test longitudinally whether these biological mechanisms mediate the PTSD- LRS relationship. The proposed study will be the first to examine mechanisms contributing to comorbidity between PTSD and LRS, a highly prevalent problem that persists despite conventional treatments. Elucidation of the etiologic pathway linking the two conditions will help to identify biomarkers which may be useful in diagnosis and for more specific, tailored, and effective treatments that target particular cells, cytokines, or genes that are altered in PTSD. The present study will also advance science by shedding light on effects of toxic disasters on human biology and hence the results will be relevant to other exposed populations, many of whom suffer from similar burdens.