Preclinical and Patient Studies of Affective Disorders in Serbia

塞尔维亚情感障碍的临床前和患者研究

• 批准号: 8619801
• 负责人: Jelena Radulovic
• 金额: $ 12.4万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-24 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8619801
• 关键词: Address; Affect; Affective; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Area; Arousal; Basic Science; Behavior; Behavioral; Blood; Blood - brain barrier anatomy; Blood specimen; Bovine Serum Albumin; Clinic; Clinical; Clinical Research; Cognitive; Cognitive deficits; Collaborations; Collection; Comorbidity; Country; Data; Dexamethasone; Diagnosis; Diagnostic; Disease; Disease model; Emotional disorder; Equipment; Exhibits; Extinction (Psychology); FK506 binding protein 5; Female; Fright; Future; Gene Expression; Genomics; Glucocorticoid Receptor; Glucocorticoids; Glutamates; Goals; Health Care Reform; Health system; Hormones; Human Resources; Injury; Institutes; Institution; Knock-out; Knockout Mice; Laboratories; Learning; Low income; Major Depressive Disorder; Mediating; Mediator of activation protein; Membrane; Memory; Mental Depression; Mental disorders; Military Personnel; Molecular; Molecular Target; Mood Disorders; Moods; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Phosphorylation; Plant Roots; Population; Post-Traumatic Stress Disorders; Pre-Clinical Model; Prevalence; Process; Protein Kinase; Psychiatry; Public Health; Receptor Signaling; Recovery; Regulation; Research; Resistance; Resources; Response Elements; Role; Serbia; Signal Pathway; Signal Transduction; Stress; Stressful Event; Symptoms; System; Testing; Time; Training; Translational Research; Trauma; Universities; Vinca; War; Woman; base; depressive symptoms; design; effective therapy; endophenotype; experience; glucocorticoid-induced orphan receptor; high risk; human RIPK1 protein; improved; learning extinction; male; men; molecular phenotype; non-genomic; novel; novel therapeutic intervention; novel therapeutics; outcome forecast; pre-clinical; preclinical study; prevent; prognostic; programs; public health relevance; receptor function; receptor sensitivity; response; sex; socioeconomics; success; tacrolimus binding protein 4; therapy design; transmission process

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.

描述（由申请人提供）：植根于最近的战争，流离失所和社会经济不稳定，塞尔维亚已经建立了创伤后应激障碍（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，一项医疗保健改革开始在不同层面解决这些问题。该提案旨在加入这一倡议，在西北大学（美国）和塞尔维亚研究所（塞尔维亚）之间建立一个合作项目，开展与主要情感障碍相关的基础和转化研究。这项合作的短期目标是通过关注新提出的β-amatergic和糖皮质激素（GC）系统之间的相互作用，开始发现PTSD的分子内表型。我们的中心假设是，N-甲基-D-天冬氨酸（NMDAR）亚基NR 2A基本上通过调节GR的非基因组和基因组作用而导致PTSD和抑郁样行为。（1）确定NR 2A缺陷在恐惧调节、抑郁和GR信号传导中的作用，（2）确定NR 2A缺陷的行为效应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发现。在完成研究后，我们期望已经确定膜不透性GC将拯救PTSD样行为背后的多巴胺能缺陷，而不加重抑郁样行为。这些资源将用于塞尔维亚创伤后应激障碍研究的能力建设，方法是培训LMIC人员，获取研究设备，并为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的主要情感障碍领域制定一个强大的翻译计划，并在合作机构之间开展跨文化研究。该研究主要旨在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。