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事件，但只有8 - 12%的人会发展为创伤后应激障碍（PTSD），这表明个体间对创伤的反应很高。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。鉴定能够捕获导致PTSD风险的遗传和环境风险的生物标志物将在指导预防干预方面大有益处;然而，目前还没有可用的生物标志物。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PTSD风险因素会导致炎症调节基因的DNA甲基化改变。高浓度的炎性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校准个体对随后创伤的生物反应，从而导致PTSD脆弱性，这是合理的。 这种关系尚未确定。这些表观遗传修饰也可能导致神经元的脆弱性，并有助于PTSD的发作。以前我们发现慢性PTSD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、海马和前扣带回的中枢GCR活性改变介导神经元脆弱性和PTSD发作。 中枢和外周GCR敏感性变化也可能导致炎症和健康相关生活质量（HRQOL）下降。为了解决这一关键问题，PI计划制定一项研究计划，以确定PTSD发作的生物学预测因子，以及PTSD发作的神经生物学基础。在第一项研究中，我们将确定预测PTSD发作的炎症调节基因中的DNA甲基化谱，这可能导致开发一种基于生物学的方法来识别PTSD风险最高的个体。在这项初步研究的第二个目的中，我们将纵向检查时间发育DNA甲基化变化，以及中枢和外周GCR敏感性和HRQOL下降的变化。我们希望这些发现能够为制定有效的预防干预措施提供信息。

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.