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

基本信息

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
项目类别：
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

项目摘要

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：我们发现抗炎细胞因子 IL-13 和 IL-4 在死亡中发挥重要作用黑质致密部 (SNc) 中的多巴胺能神经元，与人类中丢失的细胞相同该假设基于我们对小鼠的初步研究，该研究表明：白细胞介素 13 受体 α 1 链 (IL-13R¿1) 在 SNc 的 DA 神经元中高度表达，并且小鼠缺陷是该受体受到保护，免受多巴胺能（DA）神经元在发生过程中的损失。低剂量 LPS 的慢性外周注射此外，使用多巴胺能细胞系进行体外研究。结果表明，虽然 IL-13 单独使用不会对 DA 神经元产生有害影响，但它会强烈增强毒性 IL-4（另一种能够激活 IL-4 的细胞因子）也获得了类似的结果。 13R??这些结果共同表明了一种新的抗炎机制。我们建议研究我们的假设。在 SA1 中，我们将确定 IL-13（和 IL-4）信号传导之间的相互作用。在 SA2 中，氧化应激会诱导神经元损伤。在神经炎症模型中，细胞因子对体内神经元损失的影响。这些研究与了解炎症过程中 IL-13 和 IL-4 的作用高度相关。炎症在 PD 发病机制中的作用，可能会确定治疗这种疾病的新治疗靶点疾病。