Neuroinflammation and Oxidative Stress in Veterans with Schizophrenia

患有精神分裂症的退伍军人的神经炎症和氧化应激

• 批准号: 10651663
• 负责人: Yvonne S Yang
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10651663
• 关键词: Address; Affinity; Anti-Inflammatory Agents; Antioxidants; Area; Autopsy; Award; Binding; Binding Proteins; Biological Markers; Brain; Cells; Cerebrospinal Fluid; Clinical assessments; Cognition; Cognitive; Communication; Communities; Cytoprotection; Delusions; Development; Educational workshop; Enzymes; Exclusion; Foundations; Free Radicals; Functional disorder; Future; Generations; Genotype; Glutathione; Goals; Hallucinations; Housing; Immune; Inflammation; Inflammatory; Injury; Interleukin-10; Interleukin-6; Interview; K-Series Research Career Programs; Knowledge; Lead; Light; Link; Magnetic Resonance Spectroscopy; Maps; Measurement; Measures; Mentors; Microglia; Mitochondria; Natural Immunity; Neuroglia; Neurons; Noise; Occupational Status; Outcome; Oxidative Stress; Pathogenesis; Patients; Peripheral; Phenotype; Plasma; Positron-Emission Tomography; Pre-Clinical Model; Prefrontal Cortex; Process; Production; Proteins; Psychiatrist; Psychoneuroimmunology; Psychotic Disorders; Quality of life; Reactive Oxygen Species; Reporting; Role; Sample Size; Schizophrenia; Signal Transduction; Specificity; Symptoms; System; TNF gene; Techniques; Testing; Tissues; Training; United States Department of Veterans Affairs; Veterans; Vocation; Work; biomarker identification; brain based; clinically relevant; cognitive function; cognitive performance; cytokine; disability; functional outcomes; improved; inflammatory marker; meetings; neuroimaging; neuroinflammation; novel; peripheral blood; personalized medicine; radioligand; recruit; response to injury; responsible research conduct; skills; social relationships; social situation; symposium

This Veterans Affairs Career Development Award (CDA-2) proposes to examine levels of neuroinflammation and oxidative stress in the brains of Veterans with schizophrenia, and to relate these processes to each other and to important functional outcomes. Neuroinflammation, which refers to the recruitment of immune cells in response to injury, and the antioxidant defense system (AODS), which refers to the molecules and enzymes that neutralize an excess of free radicals (oxidative stress), are important protective responses to injury in the brain. Both have been shown to be altered in schizophrenia compared to healthy controls, and may be related to the pathogenesis of schizophrenia. Furthermore, their relationship to disrupted functional outcomes in schizophrenia including occupational status, housing status, and social relationships, remains relatively unstudied. Until recently, markers for neuroinflammation and the AODS have only been examined in postmortem tissue, peripheral blood, or cerebrospinal fluid (CSF) of patients. This CDA-2 proposes to examine both neuroinflammation and the AODS directly in brain of Veterans with schizophrenia and control subjects with two relatively novel techniques: 1) neuroinflammation will be measured with second-generation radioligand binding to the molecule translocator protein (TSPO), using positron emission tomography (PET); subjects will be genotyped in order to exclude the low affinity binding phenotype prior to entering the study, and 2) the AODS will be measured with levels of glutathione, the most important antioxidant molecule in the brain, using magnetic resonance spectroscopy (MRS). The specific area of focus will be dorsolateral prefrontal cortex in light of this area’s importance for cognitive function in schizophrenia. The project has three scientific goals: a) Brain levels of neuroinflammation and the AODS will be compared between patients with schizophrenia and healthy controls. b) The relationship of neuroinflammation and oxidative stress to each other in patients will be examined, along with their relationship to cognitive performance and community function via clinical assessments and interviews. c) The peripheral inflammatory markers TNF-a, IL-6, IL-10, INF-g and CRP will be measured, and their relationship to the above central markers will be examined. This information will shed light on the roles of two key processes in the brain in schizophrenia, and their influence on quality of life for Veterans with schizophrenia. In addition to these scientific aims, this proposal will provide the applicant, Dr. Yvonne Yang, with expertise in PET neuroimaging and MRS neuroimaging, and expertise in the field of neuroinflammation in schizophrenia. Dr. Yang’s training plan includes regular meetings with her mentors: expert in PET neuroimaging Dr. Mark Mandelkern, MRS physicist Dr. Albert Thomas, psychiatrist and expert in MRS of glutathione Dr. Richard Maddock, expert in psychoneuroimmunology Dr. Michael Irwin, and her primary mentor Dr. Michael Green. It also includes workshops, conferences, formal didactics, and training in the responsible conduct of research. The scientific project, training plan, and mentoring plan described above will provide Dr. Yang with the skills and expertise to independently lead further studies investigating the role of neuroinflammation in schizophrenia, and lay the groundwork for a personalized medicine treatment paradigm using anti-inflammatory and antioxidant agents, through a VA Merit Award proposal.

这个退伍军人事务职业发展奖（CDA-2）建议检查神经炎症的水平 和氧化应激在退伍军人精神分裂症患者的大脑中，并将这些过程相互联系起来 以及重要的功能性成果。神经炎症，指的是免疫细胞的募集， 抗氧化防御系统（AODS），是指抗氧化系统中的分子和酶， 中和过量的自由基（氧化应激），是重要的保护性反应， 个脑袋与健康对照组相比，精神分裂症患者的这两种基因都发生了改变， 精神分裂症的发病机制此外，他们的关系，中断功能的结果， 精神分裂症，包括职业状况，住房状况和社会关系，仍然相对 未经研究。直到最近，神经炎症和AODS的标记物仅在 患者的死后组织、外周血或脑脊液（CSF）。本CDA-2建议 直接检测退伍军人精神分裂症患者和对照组的神经炎症和AODS 受试者使用两种相对新颖的技术：1）神经炎症将用第二代 使用正电子发射断层扫描（PET），放射性配体与分子转运蛋白（TSPO）结合; 受试者将在进入研究前接受基因分型，以排除低亲和力结合表型，以及 2)AODS将用谷胱甘肽的水平来测量，谷胱甘肽是大脑中最重要的抗氧化分子， 使用磁共振波谱（MRS）。重点关注的特定区域将是背外侧前额叶 大脑皮层对精神分裂症患者认知功能的重要性。该项目有三个科学 目的：a）将在患有以下疾病的患者之间比较神经炎症和AODS的脑水平： 精神分裂症和健康对照。B）神经炎症和氧化应激与各自的关系 其他患者将被检查，沿着他们与认知表现和社区的关系 通过临床评估和访谈发挥作用。c）外周炎性标志物TNF-α、IL-6、IL-10， 将测量INF-g和CRP，并检查其与上述中心标志物的关系。这 这些信息将阐明精神分裂症大脑中两个关键过程的作用及其影响。 退伍军人精神分裂症患者的生活质量除了这些科学目标外，该提案还将提供 申请人Yvonne Yang博士具有PET神经成像和MRS神经成像方面的专业知识， 精神分裂症的神经炎症领域。杨博士的培训计划包括定期与她会面 导师：PET神经成像专家Mark Mandelkern博士，MRS物理学家Albert托马斯博士，精神病学家和 谷胱甘肽MRS专家Richard Maddock博士，心理神经免疫学专家Michael欧文博士， 她的主要导师迈克尔绿色博士它还包括讲习班、会议、正式教学法和培训 负责任地进行研究。所述的科学项目、培训计划和指导计划 以上将为杨博士提供独立领导进一步研究的技能和专业知识， 神经炎症在精神分裂症中的作用，并为个性化药物治疗奠定基础 范例使用抗炎和抗氧化剂，通过VA优异奖的建议。