Role of the IL-13 system in dopaminergic cell death

描述（由申请人提供）：我们假设抗炎细胞因子IL-13和IL-4在黑质丘脑部（SNc）多巴胺能神经元死亡中起重要作用，这些细胞在人类帕金森病（PD）中丢失。该假设基于我们在小鼠中的初步研究，该研究显示白细胞介素13受体α 1链（IL-13 Ra 1）在SNc中的DA神经元中高度表达，并且该受体缺陷的小鼠被保护免于在用低剂量LPS进行慢性外周注射期间发生的多巴胺能（DA）神经元的损失。此外，使用多巴胺能细胞系的体外研究表明，虽然单独的IL-13对DA神经元没有有害作用，但它强烈增强了轻度氧化应激的毒性。用IL-4获得了类似的结果，IL-4是另一种能够激活IL-13 Ra 1依赖性信号传导的细胞因子。总之，这些结果表明，一种新的机制，抗炎细胞因子可以有助于神经元的损失条件下的压力。我们建议在三个具体目标中研究我们的假设。在SA 1中，我们将确定IL-13（和IL-4）信号和氧化应激之间的相互作用如何在体外诱导神经元损伤。在SA 2中，我们将在神经炎症模型中研究这些细胞因子中的每一种对体内神经元损失的贡献。在SA 3中，我们将确定炎症期间IL-13和IL-4的细胞来源。这些研究与了解炎症在PD发病机制中的作用高度相关，并可能为治疗这种疾病确定新的治疗靶点。

DESCRIPTION (provided by applicant): We hypothesize that the anti-inflammatory cytokines IL-13 and IL-4 play an important role in the death of dopaminergic neurons in the Substantia nigra pars compacta (SNc), the same cells that are lost in human Parkinson's disease (PD). This hypothesis is based on our preliminary studies in mice which showed that interleukin 13 receptor alpha 1 chain (IL-13Ralpha1), is highly expressed in DA neurons in the SNc and that mice that are deficient is this receptor are protected from the loss of dopaminergic (DA) neurons that occurs during chronic peripheral injection with low doses of LPS. Furthermore, in vitro studies using a dopaminergic cell line showed that while IL-13 alone does not have harmful effects on DA neurons, it strongly potentiates the toxicity of mild oxidative stress. Similar resuls were obtained with IL-4, another cytokine capable of activating IL- 13Ralpha1-dependent signaling. Together these results suggest a novel mechanism whereby anti-inflammatory cytokines can contribute to neuronal loss under conditions of stress. We propose to investigate our hypothesis in three specific aims. In SA1, we will determine how the interaction between IL-13 (and IL-4) signaling and oxidative stress induces neuronal damage in vitro. In SA2, we will investigate the contribution of each of these cytokines to neuronal loss in vivo in a model of neuro-inflammation. In SA3, we will determine the cellular source of IL-13 and IL-4 during inflammation. These studies are highly relevant to understanding the role of inflammation in the pathogenesis of PD and may identify novel therapeutic targets for the treatment of this disease.