Rooted in recent wars, displacement, and socio-economic instability, Serbia has established a 13.5% increase in the prevalence of post-traumatic stress disorder (PTSD) and major depression, making them the second largest public health problem in this LMIC country. In parallel, the health system has deteriorated, facing multiple challenges in areas of basic and clinical research. Most recently, a health care reform has started to address these problems at different levels. This proposal aims to join this initiatie by developing a collaborative program between Northwestern University (USA) and Vinca Institute (Serbia) in basic and translational research relevant for major affective disorders. The short-term goal of this collaboration is to initiate the discovery of molecular endophenotypes of PTSD by focusing on a newly proposed interaction between the glutamatergic and glucocorticoid (GC) systems. Our central hypothesis posits that the N-methyl-D-aspartate (NMDAR) subunit NR2A essentially contributes to PTSD- and depression-like behavior by regulating the nongenomic and genomic actions of GR. We will test this hypothesis by three specific aims designed to: (1) Establish the role of NR2A deficiency in fear regulation, depression, and GR signaling, (2) Determine whether the behavioral effects of NR2A deficiency can be rescued by nongenomic or genomic GR, and (3) Initiate collection of blood samples from PTSD patients to validate the preclinical findings. After completing the study, we expect to have determined that membrane- impermeant GC will rescue the glutamatergic deficits underlying PTSD-like behavior without exacerbating depression-like behavior. The resources will be used for building capacity for PTSD research in Serbia by training LMIC personnel, acquiring research equipment, and generating pilot data for a large-scale proposal aiming to identify novel treatment, diagnostic, and prognostic molecular targets of PTSD. The long-term goal is to develop a strong translational program in Serbia in the area of major affective disorders and initiate cross-cultural studies between the collaborating institutions. The research is primarily designed to establish the use of blood molecular phenotypes for the diagnosis, prognosis, and treatment of patients suffering from major emotional disorders.

Public Health Relevance

Post-traumatic stress disorder (PTSD) has recorded a steep increase in Serbia in the past decade due to recent wars, displacement, and socio-economic instability. Similarly, the prevalence of PTSD is expected to rise significantly in the USA given the injuries in recent wars. We propose to build the capacity at the Vinca Institute (Serbia) for studies of PTSD, develop a strong cross-cultural program in basic and translational research with a laboratory at Northwestern University (USA), and thus accelerate the discovery of novel therapeutic, diagnostic, and prognostic targets for PTSD.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-BDCN-N (55))
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Meinecke, Douglas L
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Northwestern University at Chicago
Schools of Medicine
United States
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Adzic, Miroslav; Brkic, Zeljka; Mitic, Milos et al. (2018) Therapeutic Strategies for Treatment of Inflammation-related Depression. Curr Neuropharmacol 16:176-209
Lukic, Iva; Mitic, Milos; Soldatovic, Ivan et al. (2015) Accumulation of cytoplasmic glucocorticoid receptor is related to elevation of FKBP5 in lymphocytes of depressed patients. J Mol Neurosci 55:951-8
Jovicic, Milica J; Lukic, Iva; Radojcic, Marija et al. (2015) Modulation of c-Jun N-terminal kinase signaling and specific glucocorticoid receptor phosphorylation in the treatment of major depression. Med Hypotheses 85:291-4