The effects of NF-kB on oligodendrocytes in models of multiple sclerosis

NF-kB对多发性硬化症模型中少突胶质细胞的影响

• 批准号: 9268093
• 负责人: Wensheng Lin
• 金额: $ 33.25万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9268093
• 关键词: Alpha Cell; Animal Model; Astrocytes; Attenuated; Autoimmune Process; B-Cell Activation; Cell Death; Cell Survival; Cell physiology; Cells; Cessation of life; Chronic; Cuprizone; Data; Demyelinating Diseases; Demyelinations; Development; Disease; Endoplasmic Reticulum; Experimental Autoimmune Encephalomyelitis; Foundations; GTP-Binding Protein alpha Subunits, Gs; Genetic Transcription; Goals; I Kappa B-Alpha; Immune; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Interferon Type II; Interferons; Knowledge; Lesion; Mediating; Microglia; Modeling; Multiple Sclerosis; Mus; Myelin; NF-kappa B; NF-kappaB-inducing kinase; Natural Immunity; Oligodendroglia; Pancreas; Pathway interactions; Patients; Phosphotransferases; Play; Reaction; Role; Severity of illness; Signal Transduction; T-Lymphocyte; Therapeutic; Therapeutic Intervention; Transgenic Mice; Translations; Work; adaptive immunity; attenuation; axonal degeneration; cell type; cytokine; endoplasmic reticulum stress; insight; macrophage; molecular targeted therapies; mouse model; multiple sclerosis patient; novel; protective effect; response; transcription factor

Project Summary/Abstract: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease in the CNS. It is generally believed that MS and its animal model, experimental autoimmune encephalomyelitis (EAE), are initiated by an autoimmune reaction against oligodendrocytes and myelin. Evidence suggests that oligodendrocyte death induced by inflammatory attacks contributes significantly to the development of MS and EAE. Nuclear Factor κ B (NF-κB) plays a critical role in inflammatory diseases, including MS and EAE, by regulating inflammation and cell viability. Although activation of NF-κB has been observed in oligodendrocytes in MS and EAE, the effects of NF-κB on oligodendrocytes in these diseases remain largely unexplored. In vitro studies from our lab and other groups show that NF-κB activation promotes oligodendrocyte survival in response to inflammatory mediators. Our recent study shows that activation of pancreatic endoplasmic reticulum kinase (PERK) signaling in oligodendrocytes protects mice against EAE and that the protective effects of PERK signaling on oligodendrocytes during EAE are associated with NF-κB activation. Importantly, our preliminary data showed that NF-κB inactivation specifically in oligodendrocytes exacerbated interferon-γ (IFN-γ)-induced myelinating oligodendrocyte death and hypomyelination in young, developing mice. Our preliminary observation also suggested that NF-κB inactivation specifically in oligodendrocytes significantly increased EAE disease severity. Therefore, we hypothesize that NF-κB activation acts cell-autonomously to protect oligodendrocytes against inflammatory attacks in MS and EAE and accounts for the protective effects of PERK activation on oligodendrocytes in these diseases. In the first specific aim, we will determine whether NF-κB inactivation acts in a cell-autonomous manner to render (re)myelinating oligodendrocytes vulnerable to the detrimental effects of IFN-γ, a key proinflammatory cytokine in MS and EAE. In the second specific aim, we will determine whether NF-κB activation cell-autonomously protects oligodendrocytes against inflammatory attacks, resulting in attenuation of EAE disease severity. In the third specific aim, we will determine whether NF-κB activation is required for the protective effects of PERK signaling on oligodendrocytes during EAE. This work will define the cytoprotective effects of the NF-κB pathway, particularly the PERK-NF-κB pathway, on oligodendrocytes (both mature and remyelinating oligodendrocytes) in MS and EAE, which will advance our understanding of the mechanisms governing oligodendrocyte viability in MS.

项目摘要/摘要： 多发性硬化症 (MS) 是一种中枢神经系统慢性炎症性脱髓鞘疾病。人们普遍认为 MS 及其动物模型，实验性自身免疫性脑脊髓炎 (EAE)，是由自身免疫性疾病引发的。 针对少突胶质细胞和髓磷脂的反应。有证据表明少突胶质细胞死亡 炎症发作对 MS 和 EAE 的发展有显着影响。核因子 κ B (NF-κB) 通过调节炎症和细胞在炎症性疾病（包括 MS 和 EAE）中发挥关键作用 生存能力。尽管在 MS 和 EAE 的少突胶质细胞中观察到 NF-κB 的激活，但 这些疾病中少突胶质细胞上的 NF-κB 很大程度上仍未被探索。我们实验室和其他实验室的体外研究 研究小组表明，NF-κB 激活可促进少突胶质细胞响应炎症介质而存活。 我们最近的研究表明，胰腺内质网激酶（PERK）信号的激活 少突胶质细胞可保护小鼠免受 EAE 侵害，并且 PERK 信号传导对小鼠的保护作用 EAE 期间的少突胶质细胞与 NF-κB 激活相关。重要的是，我们的初步数据显示 少突胶质细胞中 NF-κB 失活会加剧干扰素-γ (IFN-γ) 诱导的髓鞘形成 年轻发育中小鼠的少突胶质细胞死亡和髓鞘形成不足。我们初步观察也 表明少突胶质细胞中 NF-κB 失活显着增加了 EAE 疾病的严重程度。 因此，我们假设 NF-κB 激活细胞自主作用，以保护少突胶质细胞免受 MS 和 EAE 中的炎症攻击以及 PERK 激活的保护作用 这些疾病中的少突胶质细胞。在第一个具体目标中，我们将确定 NF-κB 失活是否起作用 以细胞自主的方式使（重新）髓鞘化少突胶质细胞容易受到有害影响 IFN-γ，一种 MS 和 EAE 中关键的促炎细胞因子。在第二个具体目标中，我们将确定是否 NF-κB 激活细胞自主保护少突胶质细胞免受炎症攻击，从而导致 EAE 疾病严重程度的减轻。在第三个具体目标中，我们将确定 NF-κB 激活是否 EAE 期间 PERK 信号对少突胶质细胞的保护作用是必需的。这项工作将定义 NF-κB 通路，特别是 PERK-NF-κB 通路，对少突胶质细胞的细胞保护作用（两者 MS 和 EAE 中的成熟和髓鞘再生少突胶质细胞），这将增进我们对 MS 和 EAE 的理解 多发性硬化症中少突胶质细胞活力的控制机制。