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: 10364705
• 负责人: Joseph John Mann
• 金额: $ 65.49万
• 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/10364705
• 关键词: Acute; Affinity; Anterior; Autoreceptors; Behavioral; Binding; Binding Proteins; Bioenergetics; Biological Markers; Blood; Brain; Chronic; Cluster Analysis; Cognitive; Cross-Sectional Studies; DSM-V; Data; Data Set; Depressed mood; Development; Equilibrium; Exhibits; Familial disease; Free Radicals; Functional disorder; Future; Generations; Hamilton Rating Scale for Depression; Health; Inflammation; Inflammatory; Kynurenic Acid; Kynurenine; Lethargies; Link; Major Depressive Disorder; Measures; Mental Depression; 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; Tryptophan; Tryptophan 2,3 Dioxygenase; United States National Institutes of Health; Volunteer Group; Work; base; 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; patient subsets; peripheral blood; personalized medicine; radiotracer; response; serotonergic regulation; theories; trait

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.

大多数关于抑郁症（MDD）病理生理学的研究都只考察了一个单一的、假定的致病因素， 域在这项关于MDD发病机制的研究中，我们将评估三种途径之间的关系- 与MDD相关的基因域，这在很大程度上是未知的，因为这三个域从来没有被 在同一个抑郁人群中进行研究。这些结构域是：神经炎症， 失调和线粒体功能障碍。该项目是一项横向研究，将直接评估 通过使用正电子发射断层扫描（PET）测量所有三个病理生理学领域的大脑功能， 神经炎症和5-HT 1A自身受体结合，以及近红外光谱法（NIRS）来测量线粒体， MDD（N=45）和健康志愿者（HV; N=20）的脑功能。第三代高亲和力PET 示踪剂[11 C] ER 176将测量与转运蛋白（TSPO）的结合，TSPO是胶质细胞活化和线粒体的标志物。 神经功能。脑线粒体功能也将通过经颅近红外光谱进行评估- 复制（NIRS）。使用[11 C]WAY-100635进行PET将定量调节5-羟色胺神经元的5-HT 1A自身受体 发射和释放。将比较MDD组和HV组之间以及MDD内的脑测量值，因为它们 与抑郁症的严重程度有关。大脑指数也将与外周血测量相关，这将 包括犬尿氨酸途径组分、一组细胞因子/趋化因子和线粒体健康指数（MHI）， 外周线粒体功能的标量测量。这个丰富的数据集将用于生成描述性的 病理生理学领域之间的相互关系模型以及每个领域与 抑郁症状严重程度。探索性分析将寻求确定表现出不稳定性的患者亚组。 主要特异性病理学。 目的1：比较45例未经药物治疗的、抑郁的、非精神病性的DSM 5 MDD患者和20例HV患者， 在脑中体内测量的炎性、肾上腺素能和线粒体效应。确定大脑的相关性 MDD组中MDD严重程度的指标。目标2：在目标1的同一组中，确定关系- 脑TSPO结合和oxCOX活性与神经炎症的相应外周指标的关系 和线粒体功能。血细胞/趋化因子、犬尿氨酸途径组分和线粒体 健康指数（MHI）。目标3：建立描述性模型。 这项研究是创新性的，结合评估神经炎症，线粒体功能，和5- 在使用第三代TSPO放射性示踪剂的单组受试者中， 采用新的NIRS和MHI方法。该研究团队有着强大的翻译记录， 搜索与所有拟议的方式，并配备进行这项拟议的研究。从这个研究结果 将有可能统一抑郁症病理生理学的主要理论，并指导新的， 更个性化的治疗方法。