Post-traumatic stress disorder (PTSD) is an adverse psychiatric condition that occurs after exposure to extremely stressful life events. PTSD patients also develop a variety of disorders with an inflammatory component. While majority of the studies indicate that there is an excessive inflammatory state in PTSD, the precise mechanisms of immunomodulation seen during PTSD are not clear. Recently, we have made an exciting observation that the severity of PTSD is correlated with greater inflammation and a broadly dysregulated microRNA (miR) profile with numerous targets that regulate inflammatory T cell response. Specifically, we noted that numerous downregulated miRs in PTSD patients targeted components of the nuclear factor of activated T cells (NFAT) pathway, crucial for the activation, proliferation and differentiation of T cells. In addition to the NFAT proteins themselves, the serine-threonine protein phosphatase calcineurin subunits A (isoforms PPP3CA, PPP2CB, and PPP3CC) and B (isoforms PPP3R1 and PPP3R2), which activate NFAT through dephosphorylation, were found to serve as targets for numerous dysregulated miRs in PTSD patients. The status of the T cell regulation, and in particular, the NFAT pathway in PTSD has not been evaluated thus far. Based on our preliminary studies, we will test the central hypothesis that PTSD associates, at least in part, with dysregulation in the epigenetic mechanisms that alter NFAT signaling pathway leading to a pro-inflammatory state. We will pursue these studies trauma-exposed PTSD patients when compared to trauma-exposed non-PTSD controls. We will pursue 3 specific aims:
Aim 1 : We will identify the mechanisms through which miR dysregulation leads to alterations in NFAT signaling pathway leading to an inflammatory state in PTSD patients.
Aim 2 : We will determine whether PTSD triggers differential DNA methylation of specific miR and/or targets of NFAT signaling pathway components in T cells leading to pro-inflammatory response.
Aim 3 : We will test the role of histone modifications in the expression of miRs on NFAT components in PTSD patients. Together, our studies will delineate the epigenetic mechanisms underlying signaling pathways that lead to alterations in NFAT signaling and consequent T cell dysregulation and excess inflammation in PTSD patients. Our studies also aim to identify epigenetic biomarkers of PTSD that will help in the early diagnosis and treatment.

Public Health Relevance

Post-traumatic stress disorder (PTSD) is an adverse psychiatric condition commonly seen in war veterans. Our goal is to identify mechanisms outside of the genes (epigenetic) that lead to heightened immune response in veterans, which will aid in early diagnosis and treatment.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
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Gondre-Lewis, Timothy A
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University of South Carolina at Columbia
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