Preclinical and Patient Studies of Affective Disorders in Serbia

描述(申请人提供)：由于最近的战争、流离失所和社会经济不稳定，塞尔维亚的创伤后应激障碍(PTSD)和严重抑郁症的患病率增加了13.5%，使其成为这个LMIC国家的第二大公共卫生问题。与此同时，卫生系统恶化，在基础和临床研究领域面临多重挑战。最近，一项医疗改革开始在不同层面解决这些问题。这项提议旨在通过在美国西北大学和塞尔维亚芬卡研究所之间开发一个与严重情感障碍相关的基础和翻译研究的合作项目来加入这一倡议。这项合作的短期目标是通过关注新提出的谷氨酸能和糖皮质激素(GC)系统之间的相互作用来启动PTSD分子内表型的发现。我们的中心假设是，N-甲基-D-天冬氨酸(NMDAR)亚单位NR2a通过调节GR的非基因组和基因组活动，在创伤后应激障碍和抑郁样行为中起主要作用。我们将通过三个特定的目标来检验这一假说：(1)确定NR2A缺乏在恐惧调节、抑郁和GR信号中的作用；(2)确定NR2A缺乏的行为影响是否可以通过非基因组或基因组GR来挽救；以及(3)开始收集PTSD患者的血液样本，以验证临床前的研究结果。在完成这项研究后，我们预计已经确定，膜不意味着GC将挽救潜在的创伤后应激障碍样行为的谷氨酸能缺陷，而不会加剧抑郁样行为。这些资源将用于在塞尔维亚建设创伤后应激障碍研究的能力，方法是培训LMIC人员，获取研究设备，并为一项旨在确定创伤后应激障碍的新治疗、诊断和预后分子靶点的大规模提案生成试点数据。长期目标是在塞尔维亚开发一个在严重情感障碍领域的强有力的翻译计划，并启动合作机构之间的跨文化研究。这项研究的主要目的是建立血液分子表型用于诊断、预后和治疗患有严重情绪障碍的患者。

DESCRIPTION (provided by applicant): 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.