Inflammatory, mitochondrial and serotonergic interrelationships in the pathogenesis of major depression

重性抑郁症发病机制中炎症、线粒体和血清素的相互关系

• 批准号: 10579940
• 负责人: Joseph John Mann
• 金额: $ 64.79万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579940
• 关键词: Acute; Affinity; Anterior; Autoreceptors; Binding; Binding Proteins; Bioenergetics; Biological Markers; Blood; Brain; Cephalic; Chronic; Cluster Analysis; Cross-Sectional Studies; DSM-V; Data; Data Set; Depressed mood; Development; Disease remission; Equilibrium; Exhibits; Familial disease; Free Radicals; Functional disorder; Future; Generations; Hamilton Rating Scale for Depression; Health; Impaired cognition; Inflammation; Inflammatory; Kynurenic Acid; Kynurenine; Lethargies; Link; Major Depressive Disorder; Measures; Mental Depression; Meta-Analysis; Methodology; Midbrain structure; Mission; Mitochondria; Modality; Modeling; Monitor; Motivation; Mus; Near-Infrared Spectroscopy; Neurons; Oxidative Stress; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Phenotype; Population; Positron-Emission Tomography; Prefrontal Cortex; Proteins; Quinolinic Acid; Relapse; Research; Sampling; Serotonin; Serotonin Agonists; Serotonin Receptor 5-HT1A; Severities; Subgroup; Tracer; Translational Research; Tryptophan; Tryptophan 2,3 Dioxygenase; United States National Institutes of Health; Volunteer Group; Work; behavioral phenotyping; chemokine; cytochrome c oxidase; cytokine; depressed patient; depression model; depressive symptoms; glial activation; healthy volunteer; in vivo; indexing; individualized medicine; innovation; mitochondrial dysfunction; neuroinflammation; novel; novel therapeutic intervention; patient subsets; peripheral blood; personalized medicine; radiotracer; response; serotonergic regulation; theories; trait; transmission process

Most studies of major depressive disorder (MDD) pathophysiology have examined a single, putative causative domain. In this proposed study of MDD pathogenesis, we will evaluate relationships between three path- ogenic domains related to MDD, that are largely unknown because these three domains have never been studied together in a single depressed population. The domains are: neuroinflammation, serotonergic dysregulation and mitochondrial dysfunction. This project is a cross-sectional study that will directly assess brain functioning in all three pathophysiologic domains by using positron emission tomography (PET) to measure neuroinflammation and 5-HT1A autoreceptor binding, and near infrared spectrometry (NIRS) to measure mito- chondrial function, in MDD (N=45) and healthy volunteers (HV; N=20). A third-generation, high-affinity PET tracer, [11C]ER176, will measure binding to translocator protein (TSPO), a marker of glial activation and mito- chondrial function. Brain mitochondrial function also will be assessed with transcranial near infrared spectros- copy (NIRS). PET with [11C]WAY-100635 will quantify 5-HT1A autoreceptors which regulate serotonin neuron firing and release. Brain measures will be compared between MDD and HV groups and within MDD as they relate to depression severity. Brain indices also will be correlated with peripheral blood measures, which will include kynurenine pathway components, a panel of cyto/chemokines, and the mitochondrial health index (MHI), a scalar measure of peripheral mitochondrial function. This rich dataset will be used to generate descriptive models of interrelationships between pathophysiologic domains and the relative correlation of each domain with depressive symptom severity. Exploratory analyses will seek to identify subgroups of patients who exhibit do- main-specific pathology. AIM 1: Compare 45 unmedicated, depressed, non-psychotic DSM5 MDD patients with 20 HVs, on neuroinflam- matory, serotonergic and mitochondrial effects measured in vivo in brain. Determine correlations of brain measures with MDD severity in the MDD group. AIM 2: In the same groups from Aim 1, determine the relation- ships of brain TSPO binding and oxCOX activity to the respective peripheral measures of neuroinflammation and mitochondrial functioning. blood cyto/chemokines, kynurenine pathway components, and the mitochondrial health index (MHI). AIM 3: Develop descriptive models. This study is innovative in combining assessment of neuroinflammation, mitochondrial function, and 5- HT autoreceptor binding in a single set of subjects, in using a third-generation TSPO radiotracer, and in employing novel NIRS and MHI methodologies. The research team has a strong record of translational re- search with all proposed modalities and is equiped to carry out this proposed study. Findings from this study would have potential to unify major theories of depression pathophysiology, and guide the development of new, more individualized treatment approaches.

大多数主要抑郁症（MDD）病理生理学的研究都检查了一种假定的病因 领域。在这项提出的有关MDD发病机理的研究中，我们将评估三个路径之间的关系 与MDD相关的OGENIC域，这在很大程度上未知，因为这三个领域从未有过 在一个抑郁症的人群中一起研究。域是：神经炎症，血清素能 功能障碍和线粒体功能障碍。该项目是一项横断面研究，将直接评估 通过使用正电子发射断层扫描（PET）测量的所有三个病理生理领域的大脑功能 神经炎症和5-HT1A自身受体结合，以及近红外光谱法（NIRS），以测量Mito- 在MDD（n = 45）和健康志愿者（HV; n = 20）中的软骨功能。第三代高亲和力宠物 示踪剂[11C] ER176将测量与转运蛋白（TSPO）的结合，这是神经胶质激活和Mito-的标记 软骨功能。脑线粒体功能也将通过经颅近红外光谱进行评估 复制（NIRS）。具有[11C] Way-100635的PET将量化调节5-羟色胺神经元的5-HT1A自身受体 射击和释放。 MDD和HV组之间以及MDD之间将比较脑测量 与抑郁严重程度有关。大脑指标也将与外周血测量相关 包括Kynurenine途径成分，一个细胞/趋化因子小组和线粒体健康指数（MHI）， 外周线粒体功能的标量度量。这个丰富的数据集将用于生成描述性 病理生理领域之间的相互关系模型与每个领域的相对相关性与 抑郁症状严重程度。探索性分析将寻求确定表现出的患者的亚组 主要病理学。 AIM 1：比较45个未经细化的，抑郁的，非精神病的DSM5 MDD患者，具有20 HVS，在Neuroinflam- 脑体内测量的练习，血清素能和线粒体作用。确定大脑的相关性 MDD组中MDD严重程度的度量。目标2：在AIM 1的同一组中，确定关系 - 脑TSPO结合和Oxcox活性与各自神经炎症的外围度量 和线粒体功能。血细胞/趋化因子，kynurenine途径成分和线粒体 健康指数（MHI）。目标3：开发描述性模型。 这项研究在结合神经炎症，线粒体功能和5-的评估方面具有创新性。 HT自身受体在单个受试者中结合，使用第三代TSPO radiotracer和 采用新颖的NIR和MHI方法论。研究小组的翻译重新记录很强 搜索所有拟议的方式，并能够进行这项拟议的研究。这项研究的结果 将有可能统一抑郁病理生理学的主要理论，并指导新的发展 更多个性化的治疗方法。