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: 9066821
• 负责人: BRUNO CONTI
• 金额: $ 42.21万
• 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/9066821
• 关键词: 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; Health; Human; IL-13Ralpha1; IL13RA1 gene; Immune system; In Vitro; Inflammation; Injection of therapeutic agent; Interleukin-13; Interleukin-4; Knockout Mice; Ligands; 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; X Chromosome; base; cytokine; dopaminergic neuron; in vivo; neuroinflammation; neuron loss; neurotoxic; new therapeutic target; novel; pars compacta; receptor; research study

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.

描述（由申请人提供）：我们假设抗炎细胞因子IL-13和IL-4在尼格拉PARS Compacta（SNC）的多巴胺能神经元死亡中起重要作用，该细胞在人类帕金森氏病（PD）中丢失的细胞（同一细胞）。该假设基于我们在小鼠中的初步研究，该研究表明，介体13受体α1链（IL-13RALPHA1）在SNC的DA神经元中高度表达，并且缺陷的小鼠是该受体受到该受体免受多巴胺疗（DA）神经元丧失的神经元的保护，而多巴胺疗（DA）神经元在慢性peripection peripecection peripecection low persection low persection in low persection low posecection low posecection。此外，使用多巴胺能细胞系的体外研究表明，虽然仅IL-13对DA神经元没有有害影响，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RESUL，这是另一种能够激活IL-13ralpha1依赖信号传导的细胞因子。这些结果共同提出了一种新的机制，在这种机制中，抗炎细胞因子可以在压力条件下导致神经元丧失。我们建议在三个特定目标中研究我们的假设。在SA1中，我们将确定IL-13（和IL-4）信号传导与氧化应激之间的相互作用如何在体外诱导神经元损伤。在SA2中，我们将研究这些细胞因子对神经炎症模型中每种细胞因子对体内神经元丧失的贡献。在SA3中，我们将在炎症过程中确定IL-13和IL-4的细胞来源。这些研究与了解炎症在PD发病机理中的作用高度相关，并且可以鉴定出治疗该疾病的新型治疗靶标。