Post-traumatic stress disorder (PTSD) is a psychiatric condition with severe symptoms associated with biological dysregulation that can occur after exposure to shock. Exposure to trauma results in modulation in the hypothalamic-pituitary-adrenal (HPA) axis, which plays a critical role in the stress response that in turn interacts reciprocally with the immune system to maintain homeostasis. To date, over 1.6 million US men and women have served in the wars in Iraq (Operation Iraqi Freedom, OIF) and Afghanistan and surrounding regions (Operation Enduring Freedom, OEF). Over 35% of returned Iraq and Afghanistan veterans in Department of Veterans Affairs (VA) care have received mental health diagnoses, the most prevalent being PTSD. Inasmuch as, there is significant prevalence of PTSD in combat veterans who have served in the Iraq and Afghanistan wars, our studies have focused on addressing the pathological basis of immune dysfunction in these men and women. In the current study, we will test the central hypothesis that PTSD associates, at least in part, with dysregulation in the epigenetic mechanisms that control the differentiation of Th1/Th2/Th17/Treg cells of the adaptive immune response, thereby altering the cytokine profiles and promoting inflammatory response.
The specific aims are 1) to corroborate the serum cytokine profile with severity of PTSD and to determine the role of transcription factors that regulate the differentiation of Th/T reg cells. Furthermore, whether the cytokine expression in Th/Tregs is dependent on the mitogen activated protein kinase signaling pathway will be elucidated. 2) to address whether epigenetic mechanisms play a role in Th/Treg polarization by performing high-throughput microRNAs arrays and to determine the level of hypo- or hypermethylation of Th1, Th2, Th17 and Treg cytokine/transcription factor gene promoters. The miRNA data generated will be used in silico algorithms for related target gene prediction and pathways that are dysregulated. Further studies will be performed to assess whether reversal of the cytokine expression occurs in the T cells following transfection with miRNA mimics or antagomirs of miRNAs that are downregulated or upregulated respectively. Based on the methylation data, demethylation will be attempted using inhibitors for hypermethylated gene promoters of cytokines or their transcription factors to determine whether this would lead to reversal of the Th/Treg phenotypic characteristics. Together, these studies are novel in that they will not only help understand stress-induced alterations in immune profiles in PTSD patients but will also provide useful clues on whether epigenetic markers and specific cytokines/chemokines can serve as bio-markers of PTSD.

Public Health Relevance

Post-traumatic stress disorder (PTSD) is a psychiatric condition with severe symptoms associated with biological dysregulation that can occur after exposure to shock. Our studies are aimed at determining the immunological alterations induced in these patients and the underlying mechanisms so as to develop strategies for its prevention and therapy.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01MH094755-04
Application #
8662798
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Tuma, Farris K
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of South Carolina at Columbia
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Columbia
State
SC
Country
United States
Zip Code
29208
Zhou, Juhua; Chaudhry, Hina; Zhong, Yin et al. (2015) Dysregulation in microRNA expression in peripheral blood mononuclear cells of sepsis patients is associated with immunopathology. Cytokine 71:89-100
Sido, Jessica Margaret; Nagarkatti, Prakash S; Nagarkatti, Mitzi (2015) Role of Endocannabinoid Activation of Peripheral CB1 Receptors in the Regulation of Autoimmune Disease. Int Rev Immunol 34:403-14
Jackson, Austin R; Hegde, Venkatesh L; Nagarkatti, Prakash S et al. (2014) Characterization of endocannabinoid-mediated induction of myeloid-derived suppressor cells involving mast cells and MCP-1. J Leukoc Biol 95:609-19
Jackson, Austin R; Nagarkatti, Prakash; Nagarkatti, Mitzi (2014) Anandamide attenuates Th-17 cell-mediated delayed-type hypersensitivity response by triggering IL-10 production and consequent microRNA induction. PLoS One 9:e93954
Zhou, Juhua; Nagarkatti, Prakash; Zhong, Yin et al. (2014) Dysregulation in microRNA expression is associated with alterations in immune functions in combat veterans with post-traumatic stress disorder. PLoS One 9:e94075
Yang, Xiaoming; Hegde, Venkatesh L; Rao, Roshni et al. (2014) Histone modifications are associated with ?9-tetrahydrocannabinol-mediated alterations in antigen-specific T cell responses. J Biol Chem 289:18707-18
Rouse, Michael; Rao, Roshni; Nagarkatti, Mitzi et al. (2014) 3,3'-diindolylmethane ameliorates experimental autoimmune encephalomyelitis by promoting cell cycle arrest and apoptosis in activated T cells through microRNA signaling pathways. J Pharmacol Exp Ther 350:341-52
Rao, Roshni; Rieder, Sadiye Amcaoglu; Nagarkatti, Prakash et al. (2014) Staphylococcal enterotoxin B-induced microRNA-155 targets SOCS1 to promote acute inflammatory lung injury. Infect Immun 82:2971-9
Busbee, Philip B; Nagarkatti, Mitzi; Nagarkatti, Prakash S (2014) Natural indoles, indole-3-carbinol and 3,3'-diindolymethane, inhibit T cell activation by staphylococcal enterotoxin B through epigenetic regulation involving HDAC expression. Toxicol Appl Pharmacol 274:7-16
Altamemi, Ibrahim; Murphy, E Angela; Catroppo, James F et al. (2014) Role of microRNAs in resveratrol-mediated mitigation of colitis-associated tumorigenesis in Apc(Min/+) mice. J Pharmacol Exp Ther 350:99-109

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