Adaptive immune system function in depression

抑郁症中的适应性免疫系统功能

基本信息

批准号：
8409822
负责人：
RICHARD S. JOPE
金额：
$ 36.72万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-01-06 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8409822
关键词：
Address Affect Agreement Antidepressive Agents Astrocytes Autoimmune Diseases Behavior Brain CD4 Positive T Lymphocytes Catecholamines Cells Cognition Disease Exclusion Exhibits Figs - dietary Generations Glycogen Synthase Kinase 3 Goals Health High Prevalence Human Immune Immune response Immune system Immunologic Monitoring Immunosuppressive Agents In Vitro Incidence Inflammation Inflammatory Inflammatory Response Interferons Interleukin-10 Interleukin-17 Interleukin-4 Intervention Learned Helplessness Link Major Depressive Disorder Mediating Memory Mental Depression Microglia Modality Modeling Molecular Mood Disorders Moods Mus Patients Population Predisposition Process Production Reaction Recruitment Activity Regulation Regulatory T-Lymphocyte Research Design Research Personnel Role Stress System T cell response T-Cell Depletion T-Lymphocyte Testing Th2 Cells Therapeutic Therapeutic Intervention United States abstracting chemokine cytokine depressive symptoms design immune activation improved in vivo monocyte mood regulation neurogenesis neurotransmission novel response therapeutic target

Address Affect Agreement Antidepressive Agents Astrocytes Autoimmune Diseases Behavior Brain CD4 Positive T Lymphocytes Catecholamines Cells Cognition Disease Exclusion Exhibits Figs - dietary Generations Glycogen Synthase Kinase 3 Goals Health High Prevalence Human Immune Immune response Immune system Immunologic Monitoring Immunosuppressive Agents In Vitro Incidence Inflammation Inflammatory Inflammatory Response Interferons Interleukin-10 Interleukin-17 Interleukin-4 Intervention Learned Helplessness Link Major Depressive Disorder Mediating Memory Mental Depression Microglia Modality Modeling Molecular Mood Disorders Moods Mus Patients Population Predisposition Process Production Reaction Recruitment Activity Regulation Regulatory T-Lymphocyte Research Design Research Personnel Role Stress System T cell response T-Cell Depletion T-Lymphocyte Testing Th2 Cells Therapeutic Therapeutic Intervention United States abstracting chemokine cytokine depressive symptoms design immune activation improved in vivo monocyte mood regulation neurogenesis neurotransmission novel response therapeutic target

展开

项目摘要

Modified Project Summary/Abstract Section: RO1 MH095380 Novel targets need to be identified to develop new therapies for depression, a prevalent and debilitating disease often not adequately treated. The immune system is one such novel target, as substantial evidence demonstrates its involvement in depression. While previously the CNS was considered insulated from the immune system, it is now well-established that immune cells in the CNS modulate multiple processes, such as neurogenesis and cognition. The immune system includes a rapid-response innate immune system that produces cytokines and chemokines that activate and recruit the adaptive immune system, which includes T cells that possess the capacity of memory. Many CNS functions, such as cognition and mood, are affected by cytokines, but less is known about the regulation and functional effects of T cells in the CNS associated with depression. The overall hypothesis of this project is that T cells have subtype-specific regulatory effects on the susceptibility to depression and responses to antidepressants. We will examine the influences of T cell subtypes on susceptibility to depressive-like behavior, and examine the role of glycogen synthase kinase-3 (GSK3) as a regulatory mechanism linking immune responses with susceptibility to depression. These goals will identify new mechanisms by which the adaptive immune system may contribute to depression and be a novel target for therapeutic intervention. Specific Aim 1 will test the hypothesis that T cell subtype-selective actions in the brain modify depressive-like behavior. T cell depletion and transfer approaches will be used to identify consequences of T cell subtypes on susceptibility to depression-like behavior. Our Preliminary Results show accumulation of inflammatory Th1 and Th17 cells in the brains of mice exhibiting depression-like behavior, that Th1 cell depletion exacerbates depression-like behavior, that Th17 cell depletion ameliorates depression-like behavior, and that Treg repletion has antidepressant effects. Specific Aim 2 will test the hypothesis that glycogen synthase kinase-3 (GSK3) is a critical link between immune activation and susceptibility to depressive-like behavior. Our Preliminary Results show that mice expressing constitutively active GSK3 (GSK3 knockin mice) display increased susceptibility to depression-like behavior and that GSK3 drives the production of inflammatory Th17 cells. Because GSK3 promotes depression-like behavior, is linked to human depression, regulates the generation of T cell subtypes, and promotes inflammatory responses, we will apply molecular and pharmacological manipulations of GSK3 to test if GSK3's immune effects contribute to its promotion of susceptibility to depression.

修改项目摘要/摘要部分：RO1 MH095380 需要确定新的目标以开发新的抑郁症疗法，这种抑郁症的疾病通常不足以治疗。免疫系统是这样一个新的目标，因为大量证据表明其参与抑郁症。虽然以前认为中枢神经系统被认为是与免疫系统隔离的，但现在已经良好地确定了中枢神经系统中的免疫细胞调节多个过程，例如神经发生和认知。免疫系统包括一种快速反应的先天免疫系统，该系统会产生细胞因子和趋化因子，从而激活和募集适应性免疫系统，其中包括具有记忆能力的T细胞。许多CNS功能（例如认知和情绪）受细胞因子的影响，但对与抑郁症相关的中枢神经系统中T细胞的调节和功能效应知之甚少。该项目的总体假设是T细胞对抑郁症的易感性和对抗抑郁药的反应具有亚型特异性调节作用。我们将研究T细胞亚型对抑郁样行为敏感性的影响，并检查糖原合酶激酶3（GSK3）作为将免疫反应与抑郁症易感性联系起来的调节机制的作用。这些目标将确定自适应免疫系统可能导致抑郁症的新机制，并成为治疗干预的新目标。具体目标1将检验以下假设：大脑中T细胞亚型选择性作用改变了抑郁样行为。 T细胞的耗竭和转移方法将用于确定T细胞亚型对抑郁症状行为的敏感性的后果。我们的初步结果表明，炎症性Th1和Th17细胞在表现出类似抑郁症行为的小鼠的大脑中的积累，Th1细胞的耗竭加剧了抑郁症的行为，Th17细胞的耗竭可以缓解抑郁症样的行为，而TREG的抑制作用则可以减轻抑郁症的行为，而TREG的抑制作用则具有抗抑郁作用。具体目标2将检验以下假设：糖原合酶激酶3（GSK3）是免疫激活与抑郁样行为敏感性之间的关键联系。我们的初步结果表明，表达组成型活性GSK3（GSK3敲击蛋白小鼠）的小鼠表现出对抑郁样行为的敏感性增加，而GSK3驱动炎症性Th17细胞的产生。由于GSK3促进了类似抑郁症的行为，与人类抑郁症有关，调节T细胞亚型的产生并促进炎症反应，因此我们将应用GSK3的分子和药理学操纵来测试GSK3是否有助于促进其对抑郁症的易感性的影响。