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.

大多数关于重度抑郁症（MDD）病理生理学的研究都只检查了单一的、假定的病因