Role of the IL-13 system in dopaminergic cell death

IL-13系统在多巴胺能细胞死亡中的作用

• 批准号: 8612661
• 负责人: BRUNO CONTI
• 金额: $ 44.01万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8612661
• 关键词: Abbreviations; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Brain; Cell Death; Cell Line; Cells; Cessation of life; Chronic; Cytokine Signaling; Disease; Dopaminergic Cell; Dose; Functional disorder; Genes; Human; IL-13Ralpha1; Immune system; In Vitro; Inflammation; Injection of therapeutic agent; Interleukin-13; Interleukin-4; Interleukins; Knockout Mice; Ligands; Lipopolysaccharides; Mediating; Mediator of activation protein; Microglia; Modeling; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oxidative Stress; Parkinson Disease; Pathogenesis; Peripheral; Play; Predisposition; Reactive Oxygen Species; Reporter; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Source; Stress; Substantia nigra structure; System; Testing; Toxic effect; Transgenic Mice; Tyrosine 3-Monooxygenase; X Chromosome; base; cytokine; dopaminergic neuron; human IL13RA1 protein; in vivo; interleukin-13 receptor; male; neuroinflammation; neuron loss; neurotoxic; new therapeutic target; novel; pars compacta; public health relevance; receptor; research study

Project Summary/Abstract: 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-13R¿1), 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 results were obtained with IL-4, another cytokine capable of activating IL- 13R¿1-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.

项目摘要/摘要： 我们推测，抗炎细胞因子IL-13和IL-4在猪的死亡中起重要作用。 黑质致密部(SNC)中的多巴胺能神经元，与人类丢失的细胞相同 帕金森氏病(PD)。这一假设是基于我们对小鼠的初步研究，该研究表明 白介素13受体α1链(IL-13R？1)在黑质和小鼠的DA神经元中高表达 有缺陷的是这种受体被保护免受多巴胺(DA)神经元的损失 慢性外周注射小剂量内毒素。此外，使用多巴胺能细胞系进行的体外研究 研究表明，虽然IL-13单独对DA神经元没有有害影响，但它强烈地增强了毒性 轻微的氧化应激。另一种能够激活IL-4的细胞因子IL-4也得到了类似的结果。 13R？1依赖的信号转导。综上所述，这些结果表明了一种新的抗炎机制 在应激条件下，细胞因子可导致神经元丢失。我们打算调查一下我们的假设 有三个具体目标。在SA1中，我们将确定IL-13(和IL-4)信号和 氧化应激在体外诱导神经元损伤。在SA2中，我们将调查其中每一项的贡献 在神经炎症模型中细胞因子与体内神经元丢失的关系。在SA3中，我们将确定细胞 炎症时IL-13和IL-4的来源。这些研究与理解人类免疫缺陷的作用密切相关 炎症在帕金森病发病机制中的作用及寻找治疗该疾病的新靶点 疾病。