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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：
10602452
负责人：
Eleonore Beurel
金额：
$ 38.38万
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/10602452
关键词：
Address Adoptive Cell Transfers Adoptive Transfer Affect American Antibodies Antidepressive Agents Astrocytes Autoimmune Diseases B-Lymphocytes BLR1 gene Bacteria Behavior Blood Brain Brain region CCR6 gene CD4 Positive T Lymphocytes Cells Characteristics Chronic Clinical Communication Cytolysis Data Development Disease Drug Delivery Systems Engineering Escherichia coli Exhibits Flow Cytometry Grant Hippocampus IL17 gene Individual Infiltration Inflammation Inflammatory Inflammatory Response 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 Patients Peripheral Persons Predisposition Prefrontal Cortex Production Psoriasis Regulatory T-Lymphocyte Research Rheumatoid Arthritis Rodent Role Scheme Signal Transduction Source Sphingosine-1-Phosphate Receptor Stress T cell infiltration T cell receptor repertoire sequencing T-Cell Receptor T-Lymphocyte T-cell receptor repertoire Testing Therapeutic Transgenic Mice VAI-2 Visualization Wild Type Mouse antagonist anti-CD20 antidepressant effect biomarker identification 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 side effect therapeutic target

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.

项目概要迫切需要了解抑郁症的原因，以便开发有效的治疗方法目前有 11% 的美国人患有这种使人衰弱的疾病。该项目重点关注一个新的目标，辅助 T 17 (Th17) 细胞，我们最近将其与小鼠模型中的抑郁症易感性联系起来并为此我们确定了可行的干预措施。该项目的总体目标是确定表征、定位和识别 Th17 细胞在应激后的作用机制并测试其潜力靶向 Th17 细胞以降低抑郁症易感性的治疗效果，评估如下：测量小鼠的抑郁样行为。这项研究是从现在已确立的链接演变而来的介于炎症和抑郁之间。我们推断治疗靶向下游，并且长期而言，炎症的结果可能比试图中和大量的病毒更可行在对应激的炎症反应中短暂诱导的细胞因子。炎症细胞因子与抑郁症相关的 Th17 细胞的产生，而 Th17 细胞已经很好地已确定对中枢神经系统有毒。在小鼠模型中，我们发现 Th17 细胞能够浸润应激后小鼠脑实质中，这些浸润细胞表现出致病性特征 (CCR6+ 和 IL-23R+) 和滤泡 (CXCR5+) Th17 细胞，并且 Th17 细胞上 CCR6 的存在他们需要促进习得性无助。我们还确定肠道是一个可能的来源浸润 Th17 细胞，当小鼠接受来自表达 T 细胞受体的转基因小鼠的 CD4 细胞时（TCR）特定于分段丝状细菌足以促进习得性无助，而野生型小鼠的 CD4 细胞则不然。然而，Th17 细胞的作用机制抑郁症尚不清楚。在该项目中，具体目标 1 将确定 Th17 细胞的特征促进抑郁样行为。我们将确定与 Th17 细胞定位相关的因素压力后的大脑。具体目标 2 将确定大脑中 Th17 细胞的作用促进抑郁样行为。使用消耗方法，我们将识别下游细胞 Th17 细胞的效应器负责抑郁样行为。具体目标 3 将决定 Th17 是否可以靶向细胞来诱导抗抑郁作用。我们将测试是否使用以下方法阻断 Th17 细胞：纳米粒子和工程细菌足以诱导抗抑郁作用。总共这个项目将确定Th17的定位、来源、特征和作用机制细胞的抑郁样行为，并确定 Th17 细胞生产的目标策略可以阻止压力后的压力，从而开发出一种新的抑郁症治疗策略，流行的、使人衰弱的、治疗不充分的疾病。

项目成果

期刊论文数量（30）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Inflammatory Aspect of Male and Female Pattern Hair Loss.

DOI：
10.2147/jir.s275785
发表时间：
2020
期刊：
Journal of inflammation research
影响因子：
4.5
作者：
Peyravian N;Deo S;Daunert S;Jimenez JJ
通讯作者：
Jimenez JJ

Ketamine-induced inhibition of glycogen synthase kinase-3 contributes to the augmentation of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor signaling.

DOI：
10.1111/bdi.12436
发表时间：
2016-09
期刊：
Bipolar disorders
影响因子：
5.4
作者：
Beurel E;Grieco SF;Amadei C;Downey K;Jope RS
通讯作者：
Jope RS

Up-regulation of insulin-like growth factor 2 by ketamine requires glycogen synthase kinase-3 inhibition.

DOI：
10.1016/j.pnpbp.2016.08.008
发表时间：
2017-01-04
期刊：
PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY
影响因子：
5.6
作者：
Grieco, Steven F.;Cheng, Yuyan;Eldar-Finkelman, Hagit;Jope, Richard S.;Beurel, Eleonore
通讯作者：
Beurel, Eleonore

Th17 cells in depression.