Th17 cells as a new therapeutic target for depression

项目摘要 有一个至关重要的需要了解抑郁症的原因，以制定有效的治疗方法， 目前有11%的美国人患有这种使人衰弱的疾病。该项目的重点是一个新的 靶向辅助性T细胞17（Th 17），我们最近在小鼠模型中将其与抑郁症易感性联系起来 并且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、定位和鉴定应激后Th 17细胞的作用机制，并测试其潜力 靶向Th 17细胞以降低抑郁症易感性的治疗影响，通过 测量小鼠的抑郁样行为。这项研究是从现在已经建立的联系发展而来的， 炎症和抑郁症之间的联系我们推断，治疗靶向下游， 长期的，炎症的结果可能比试图中和大量的 在应激的炎症反应中瞬时诱导的细胞因子。炎性细胞因子 与抑郁症相关的驱动Th 17细胞的产生，而Th 17细胞已经很好地 已确定对CNS有毒。在小鼠模型中，我们发现Th 17细胞能够浸润 在应激后的小鼠脑实质中，这些浸润细胞表现出致病性的特征， (CCR6+和IL-23 R+）和滤泡（CXCR 5+）Th 17细胞，并且CCR 6在Th 17细胞上的存在是 需要他们来促进习得性无助。我们还发现肠道可能是 浸润性Th 17细胞，如接受来自表达T细胞受体的转基因小鼠的CD 4细胞的小鼠 (TCR)特定于节段性丝状细菌的药物足以促进习得性无助， 而野生型小鼠的CD 4细胞则没有。然而，Th 17细胞在肿瘤细胞中的作用机制尚不清楚。 抑郁症仍不清楚。在本项目中，特异性目标1将确定Th 17细胞的特性 会导致类似抑郁的行为我们将确定与Th 17细胞定位相关的因素， 压力后的大脑具体目标2将决定Th 17细胞在大脑中的作用， 促进抑郁样行为。使用耗尽方法，我们将确定下游单元格 Th 17细胞的效应子负责抑郁样行为。具体目标3将确定Th 17是否 可以靶向细胞以诱导抗抑郁作用。我们将测试是否使用 纳米颗粒和工程细菌足以诱导抗抑郁作用。总之， 项目将确定Th 17的定位、来源、特性和作用机制 细胞在抑郁样行为，并确定有针对性的策略，通过该Th 17细胞的生产 为了开发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。

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.