Deciphering Biological Linkages Between PTSD and Respiratory Disease in WTC Respo

在 WTC Respo 解读 PTSD 与呼吸系统疾病之间的生物联系

• 批准号: 8777847
• 负责人: BENJAMIN J LUFT
• 金额: $ 99.83万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8777847
• 关键词: Deciphering; Biological; Linkages; Between; PTSD

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.

描述（由适用提供）：2001年9月11日，恐怖袭击世界旅行中心是一场非凡的环境灾难，导致身体和情感创伤的前所未有的结合对救援和恢复工人。结果，十年后，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，多达十年后，有多达60％的应答者经历了临床上重要的症状。我们由NIOSH资助的研究计划的重点是理解这种合并症在WTC响应者及其基本机制中的大小和影响，以确定更有效的诊断生物标志物和治疗性干预措施。 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 PTSD/LRS的基本关系是为了揭示机制，我们确认了Uddin等人（NIOSH授予U01OH010416）的表观遗传变化。 PTSD的反应者。这些基因中的脱甲基化也与LRS相关。现在，我们的位置良好，以利用我们先前的NIOSH资助研究来实现拟议的两年时间范围内的以下特定目标：1）确定淋巴细胞和单核细胞免疫细胞中的差异DNA甲基化模式在具有和不具有PTSD的情况下的反应中。我们将确定特定的WTC暴露，PTSD症状，合并症的精神病和特定呼吸系统疾病是否与这些表观遗传差异有关。 2）将与PTSD相关的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相关联，以确定表观遗传差异的下游效应。 3）在获得生物样品后2年评估参与者的健康结果，以确定甲基化，基因表达和炎性细胞因子的水平是否有助于LRS的发作和持久性。我们还将纵向测试这些生物学机制是否介导PTSD-LRS关系。拟议的研究将是第一个检查有助于PTSD和LRS合并症的机制，这是一个非常普遍的问题，它持续了目的地常规处理。阐明将两种疾病联系起来的病因途径将有助于鉴定可能在诊断和更具体，定制和有效的治疗方法中有用的生物标志物，以靶向特定细胞，细胞因子或PTSD中改变的基因。本研究还将通过阐明有毒灾害对人类生物学的影响，从而推进科学，因此结果将与其他暴露的人群有关，其中许多人患有类似的伯伦斯。