Th17 cells as a new therapeutic target for depression

项目摘要 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%的美国人患有这种令人衰弱的疾病。这个项目关注的是一种新的 靶T辅助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 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、定位和鉴定Th17细胞在应激后的作用机制并测试其潜能 通过评估靶向Th17细胞以降低抑郁易感性的治疗效果 测量小鼠的抑郁样行为。这项研究是从现在已经确立的联系发展而来的 在炎症和抑郁之间。我们认为，从治疗的角度来看，下游的目标是 长期的炎症结果可能比试图中和人群更可行 在对应激的炎症反应中短暂诱导的细胞因子。炎性细胞因子 与抑郁相关的驱动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性。在小鼠模型中，我们发现Th17细胞能够渗透 小鼠脑实质应激后，这些浸润性细胞表现出致病特性 (CCR6+和IL-23R+)和滤泡(CXCR5+)Th17细胞，而CCR6在Th17细胞上的存在是 这是他们促进习得性无助所必需的。我们还确认内脏可能是 渗透Th17细胞，如小鼠接受来自表达T细胞受体的转基因小鼠的CD4细胞 丝状细菌片段特异性(TCR)足以促进习得性无助， 而野生型小鼠的CD4细胞则不是。然而，Th17细胞在慢性粒细胞白血病中的作用机制 抑郁症仍不清楚。在这个项目中，特定的目标1将确定Th17细胞的特征 这会促进类似抑郁的行为。我们将确定与Th17细胞定位相关的因素 压力过后的大脑。特定目标2将决定大脑中Th17细胞的活动， 促进类似抑郁的行为。使用耗尽方法，我们将识别下游细胞 Th17细胞的效应器，负责类似抑郁的行为。具体目标3将决定Th17是否 细胞可以被靶向诱导抗抑郁作用。我们将测试是否通过使用 纳米颗粒和工程菌足以诱导抗抑郁作用。总而言之，这 项目将确定Th17的本地化、来源、特征和作用机制 抑郁样行为中的细胞并确定Th17细胞产生的靶向策略 为了开发一种新的治疗抑郁症的策略，可以阻止紧张性应激 疾病流行的、使人衰弱的和治疗不充分的疾病。

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.