Th17 cells as a new therapeutic target for depression

 描述（由申请人提供）：有一个至关重要的需要，以了解抑郁症的原因，以制定有效的治疗方法，为9%的美国人谁目前患有这种衰弱的疾病。该项目的重点是一个新的目标，T辅助细胞17（Th 17）细胞，我们最近在小鼠模型中将其与抑郁症易感性联系起来，并确定了可行的干预措施。该项目的总体目标是确定调节Th 17细胞产生的机制，并测试靶向Th 17细胞以降低抑郁症易感性的潜在治疗影响，通过测量小鼠的抑郁样行为进行评估。这项研究是从炎症和抑郁症之间现已确立的联系发展而来的。我们推断，治疗靶向下游和长期的炎症结果可能比试图中和在对压力的炎症反应中瞬时诱导的大量细胞因子更可行。与抑郁症相关的炎性细胞因子驱动Th 17细胞的产生，并且Th 17细胞已经被公认为对CNS有毒。在小鼠模型中，我们发现在诱导抑郁样状态期间，Th 17细胞在大脑中积累，Th 17细胞的施用足以增加对抑郁样结果的脆弱性，并且消除Th 17细胞的产生或作用提供了对抑郁样应激结果的强大抵抗力。因此，现在至关重要的是要确定控制Th 17细胞的产生和作用的机制，以阻碍其促增殖作用。值得注意的是，我们发现糖原合成酶激酶-3（GSK 3），一种已知促进抑郁症易感性的酶，驱动了Th 17细胞的产生。抑制GSK 3在体外和体内多种条件下阻断了Th 17细胞的产生，并降低了小鼠对应激诱导的抑郁样结果的易感性。在这个项目中，Specific Aim 1将确定GSK 3在抑郁症期间控制Th 17细胞产生的机制。我们将鉴定参与由GSK 3调节的Th 17细胞分化的转录因子，以及调节这些细胞中GSK 3诱导的表达，并鉴定抑郁诱导的Th 17细胞的特征。具体目标2将测试靶向Th 17细胞的亚型是否增加小鼠的抵抗力和抑郁样行为的恢复。使用纳米颗粒偶联药物和GSK 3 siRNA，以及GSK 3 β耗尽T细胞的转基因小鼠，我们将确定新的干预机制，副作用最小。具体目标3将检验由Th 17细胞产生的IL-17 A介导小鼠对抑郁样行为的易感性增加的假设。总而言之，该项目将确定Th 17细胞促进抑郁样结果的机制，并确定应激后Th 17细胞产生被阻断的机制，以开发针对抑郁症（一种普遍存在、使人衰弱且治疗不足的疾病）的新治疗策略。

 DESCRIPTION (provided by applicant): There is a vital need to understand the causes of depression in order to develop effective treatments for the 9% 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 mechanism regulating Th17 cell production 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 accumulate in the brain during induced depression-like states, that administration of Th17 cells was sufficient to increase vulnerability to depression-like outcomes and that ablating the production or actions of Th17 cells provided strong resistance to depression-like outcomes of stress. Thus, it is now critical to identify mechanisms that control the production and effects of Th17 cells to obstruct their pro-depressant actions. Remarkably, we found that glycogen synthase kinase-3 (GSK3), an enzyme already known to promote depression susceptibility, drives the production of Th17 cells. Inhibition of GSK3 blocked Th17 cell production in vitro and in vivo in a variety of conditions, and reduced susceptibility to stress-induced depression-like outcomes in mice. In this project, Specific Aim 1 will determine the mechanisms by which GSK3 controls Th17 cell production during depression. We will identify transcription factors involved in Th17 cell differentiation regulated by GSK3, and regulating GSK3 induced expression in these cells, and identify characteristics of depression-induced Th17 cells. Specific Aim 2 will test if targeting subtypes of Th17 cells increases resistance and recovery of depression-like behavior in mice. Using nanoparticle-coupled drugs and GSK3 siRNA, and transgenic mice with GSK3ß-depleted T cells, we will identify new interventions mechanisms with minimal side effects. Specific Aim 3 will test the hypothesis that IL-17A that is produced by Th17 cells mediates increased susceptibility to depression-like behaviors in mice. Altogether this project will identify the mechanisms how Th17 cells promotes depression-like outcomes and determine mechanisms 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.