Investigation of the Central and Peripheral Inflammatory Mechanisms of PTSD Onset

描述（由申请人提供）：高达90%的美国人经历过创伤性事件，但只有8%至12%的人会发展为创伤后应激障碍（PTSD），这表明对创伤有高度的个体间反应。造成这种异质性的原因无疑是多因素的，涉及遗传和环境因素之间复杂的相互作用，我们才刚刚开始了解。识别能够捕捉导致PTSD风险的遗传和环境风险的生物标志物将对指导预防性干预有很大好处；然而，目前还没有可用的。我们假设DNA甲基化可能是一种理想的生物标志物，因为预先存在的创伤后应激障碍风险因素会导致炎症调节基因的DNA甲基化改变。高浓度的炎症细胞因子和内分泌调节不足与PTSD的发病有关。因此，表观遗传修饰有助于重新调整个体对后续创伤的生物反应，从而导致PTSD易感性，这是合理的。这种关系是不确定的。这些表观遗传修饰也可能导致神经易感性，并有助于PTSD的发病。以前我们发现慢性创伤后应激障碍与炎症有关，炎症与糖皮质激素（GCR）敏感性的改变有关。临床前模型中杏仁核、海马和前扣带中枢GCR活性的改变介导神经元易感性和PTSD发病。中枢和外周GCR敏感性的改变也可能导致炎症和健康相关生活质量（HRQOL）的下降。为了解决这一关键问题，PI计划制定一个研究项目，以确定PTSD发病的生物学预测因素，以及PTSD发病的神经生物学基础。在第一项研究中，我们将确定预测PTSD发病的炎症调节基因中的DNA甲基化谱，这可能会导致基于生物学的方法的发展，以识别PTSD最高风险的个体。在本初步研究的第二个目的中，我们将纵向检查发育时间DNA甲基化变化，中枢和外周GCR敏感性的变化以及HRQOL的下降。我们希望这些发现能够为有效的预防干预措施的发展提供信息。

DESCRIPTION (provided by applicant): Up to 90% of Americans experience a traumatic event, yet only 8 to 12% will then develop post-traumatic Stress disorder (PTSD), indicating that there is a high-level of inter-individual response to a trauma. The reasons for this heterogeneity are undoubtedly multi-factorial, and involve a complex interplay between genetic and environmental factors, that we are only starting to understand. Identification of biomarkers that are able to capture the genetic and environmental risks that contribute to PTSD risk would be of great benefit in directing preventive interventions; however, there are none currently available. We postulate that DNA methylation may be an ideal biomarker, as pre-existing PTSD risk factors result in altered DNA methylation of inflammatory regulating genes. High concentrations of inflammatory cytokines and insufficient endocrine regulation have been linked to PTSD onset. Therefore, it is plausible that epigenetic modifications serve to recalibrate an individual's biological response to a subsequent trauma, contributing to PTSD vulnerability. This relationship is not determined. These epigenetic modifications may also result in neuronal vulnerability, and contribute to PTSD onset. Previously we show that chronic PTSD is associated with inflammation which relates to alterations in glucocorticoid (GCR) sensitivity. Altered central GCR activity in the amygdala, hippocampus and anterior cingulate in preclinical models mediates neuronal vulnerability and PTSD onset. Central and peripheral GCR sensitivity changes may also contribute to inflammation and declines in health related quality of life (HRQOL). To address this critical issue the PI plans to develop a program of research to determine the biological predictors of PTSD onset, and the neurobiology that underlies PTSD onset. In this first study we will determine DNA methylation profiles in inflammatory regulating genes that predict PTSD onset, which may lead to the development of a biologically based method to identify individuals at highest risk for PTSD. In the second aim of this initial study, w will longitudinally examine the temporal development DNA methylation changes, and alterations in central and peripheral GCR sensitivity and HRQOL declines. We expect these findings to inform the development of effective preventative interventions.