Investigation of the Central and Peripheral Inflammatory Mechanisms of PTSD Onset

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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.