Th17 cells as a new therapeutic target for depression

 描述(申请人提供)：迫切需要了解抑郁症的原因，以便为目前患有这种衰弱疾病的9%的美国人开发有效的治疗方法。该项目专注于一种新的靶点，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，并确定了可行的干预措施。该项目的总体目标是确定调节Th17细胞产生的机制，并通过测量小鼠的抑郁样行为来测试靶向Th17细胞以降低抑郁易感性的潜在治疗效果。这项研究是从现在公认的炎症和抑郁之间的联系发展而来的。我们认为，以炎症的下游和长期结果为治疗靶点，可能比试图中和应激反应中瞬时诱导的多种细胞因子更可行。与抑郁相关的炎性细胞因子驱动Th17细胞的产生，而Th17细胞已经被证实对中枢神经系统有毒性。在小鼠模型中，我们发现Th17细胞在诱导的抑郁样状态下在大脑中积累，给予Th17细胞足以增加对抑郁样结果的易感性，并且消融Th17细胞的产生或活动提供了对应激抑郁样结果的强大抵抗。因此，现在至关重要的是确定控制Th17细胞的产生和影响的机制，以阻止它们的亲抑郁作用。值得注意的是，我们发现糖原合成酶激酶-3(GSK3)，一种已知的促进抑郁症易感性的酶，驱动Th17细胞的产生。抑制GSK3在各种条件下在体外和体内阻断Th17细胞的产生，并降低小鼠对应激诱导的抑郁样结果的易感性。在这个项目中，特定的目标1将确定GSK3在抑郁期间控制Th17细胞产生的机制。我们将确定参与GSK3调控的Th17细胞分化的转录因子，并调控GSK3在这些细胞中的表达，并鉴定抑郁诱导的Th17细胞的特征。特定目标2将测试靶向Th17细胞亚型是否会增加小鼠对抑郁样行为的抵抗力和恢复。使用纳米颗粒偶联药物和GSK3 siRNA，以及GSK3ü缺失T细胞的转基因小鼠，我们将确定副作用最小的新干预机制。具体目标3将测试假设，即由Th17细胞产生的IL-17A介导了小鼠对抑郁样行为的易感性增加。总之，该项目将确定Th17细胞如何促进抑郁症样结果的机制，并确定在应激后Th17细胞产生被阻断的机制，以开发一种新的治疗抑郁症的策略，抑郁症是一种普遍存在的、虚弱的、未得到充分治疗的疾病。

 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.