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.

项目概要/摘要： 我们推测，抗炎细胞因子IL-13和IL-4在肺腺癌的死亡中起重要作用。 黑质神经元（SNc）中的多巴胺能神经元，与人类中丢失的细胞相同 帕金森病（PD）。这一假设是基于我们对小鼠的初步研究，研究表明， 白细胞介素13受体α 1链（IL-13 R1）在黑质神经元中高度表达， 缺乏的是这种受体被保护免受多巴胺能（DA）神经元的损失， 慢性外周注射低剂量LPS。此外，使用多巴胺能细胞系的体外研究 表明，虽然IL-13单独对DA神经元没有有害作用，但它强烈增强了毒性。 轻度氧化应激用另一种能够激活IL-4的细胞因子IL-4也得到了类似的结果。 13 R1依赖性信号传导。总之，这些结果表明了一种新的机制， 细胞因子可在应激条件下导致神经元损失。我们建议调查我们的假设 三个具体目标。在SA 1中，我们将确定IL-13（和IL-4）信号传导与IL-13之间的相互作用， 氧化应激诱导体外神经元损伤。在SA 2中，我们将研究这些因素中的每一个的贡献 在神经炎症模型中，细胞因子对体内神经元损失的影响。在SA 3中，我们将确定 炎症过程中IL-13和IL-4的来源。这些研究对于理解 炎症在PD的发病机制，并可能确定新的治疗靶点，用于治疗这种疾病。 疾病