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Th17 cells as a new therapeutic target for depression

Th17细胞作为抑郁症的新治疗靶点

基本信息

批准号：
10186821
负责人：
Eleonore Beurel
金额：
$ 34.59万
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：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10186821
关键词：
Address Adoptive Cell Transfers Adoptive Transfer Affect American Antibodies Antidepressive Agents Astrocytes Autoimmune B-Lymphocytes BLR1 gene Bacteria Behavior Blood Brain Brain region CCR6 gene CD4 Positive T Lymphocytes Cells Characteristics Chronic Clinical Cytolysis Data Development Disease Drug Delivery Systems Engineering Escherichia coli Exhibits Flow Cytometry Grant Hippocampus (Brain)Individual Inflammation Inflammatory Inflammatory Response Interleukin-17 Intervention Knock-out Label Lead Learned Helplessness Link Major Depressive Disorder Maps Measures Mental Depression Mental disorders Microglia Modeling Multiple Sclerosis Mus Nature Neurodegenerative Disorders Neurons Outcome Pathogenicity Peripheral Predisposition Prefrontal Cortex Production Regulatory T-Lymphocyte Research Rheumatoid Arthritis Rodent Role Scheme Side Signal Transduction Source Sphingosine-1-Phosphate Receptor Stress Stress Tests T cell receptor repertoire sequencing T-Cell Receptor T-Lymphocyte T-cell receptor repertoire Testing Therapeutic Transgenic Mice VAI-2 Wild Type Mouse anti-CD20 antidepressant effect brain parenchyma cell killing connectome cytokine depression model depressive symptoms effective therapy effector T cell efficacious treatment improved insight mouse model nanobodies nanoparticle new therapeutic target novel therapeutic intervention prevent quorum sensing restraint stress therapeutic target transcriptome sequencing

项目摘要

Project Summary There is a vital need to understand the causes of depression in order to develop effective treatments for the 11% of Americans who currently suffer from this debilitating disease. This project focuses on a new target, T helper 17 (Th17) cells, which we recently linked to depression susceptibility in mouse models and for which we identified feasible interventions. The overall objectives of this project are to identify characterize, localize and identify mechanisms of action of Th17 cells after stress and test the potential therapeutic impact of targeting Th17 cells to decrease vulnerability to depression, assessed by measuring depression-like behaviors in mice. This research evolved from the now well-established link between inflammation and depression. We reasoned that therapeutically targeting downstream, and prolonged, outcomes of inflammation may be more feasible than attempting to neutralize the multitude of cytokines that are transiently induced in the inflammatory response to stress. Inflammatory cytokines associated with depression drive the production of Th17 cells, and Th17 cells are already well- established to be toxic to the CNS. In mouse models, we found that Th17 cells are able to infiltrate mouse brain parenchyma after stress, these infiltrating cells exhibited characteristics of pathogenic (CCR6+ and IL-23R+) and follicular (CXCR5+) Th17 cells, and the presence of CCR6 on Th17 cells was required for them to promote learned helplessness. We also identified the gut as a likely source of infiltrating Th17 cells, as mice receiving CD4 cells from transgenic mice that express T cell receptor (TCR) specific for Segmented Filamentous Bacterium are sufficient to promote learned helplessness, whereas CD4 cells from wild-type mice are not. However, the mechanisms of action of Th17 cells in depression remain unclear. In this project, Specific Aim 1 will determine the characteristics of Th17 cells that promote depressive-like behaviors. We will identify factors associated with Th17 cell localization in the brain after stress. Specific Aim 2 will will determine the actions of Th17 cells in the brain that promote depressive-like behaviors. Using depleting approaches, we will identify the downstream cell effectors of Th17 cells responsible for depressive-like behaviors. Specific Aim 3 will determine if Th17 cells can be targeted to induce antidepressant effects. We will test if blocking Th17 cells using nanoparticles and engineered bacteria is sufficient to induce antidepressant actions. Altogether this project will identify the localization, the source, the characteristics and the mechanisms of action of Th17 cells in depressive-like behaviors and determine targeted strategy by which Th17 cell production following stress can be blocked in order to develop a new therapeutic strategy for depression, a prevalent, debilitating, and inadequately treated disease.

项目总结