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Role of immunoproteasome in airway viral infection

Role of immunoproteasome in airway viral infection
免疫蛋白酶体在气道病毒感染中的作用
批准号:
10398121
负责人:
Hong W Chu
金额:
$55.59万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-05-01 至 2025-04-30

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中文摘要
翻译
项目摘要/摘要 这项建议的目的是确定免疫蛋白酶体(IP)的调节和功能 伴有2型炎症的呼吸道鼻病毒感染,这是2型炎症(如白细胞介素13[IL-13])升高的标志 哮喘。鼻病毒(RV)感染仍然是一个重大的医疗负担,因为它导致了病情恶化 哮喘和其他肺部疾病。由于目前还没有有效的治疗呼吸道轮状病毒感染的方法,因此迫切需要 定义新的机制(例如,IP),以清除RV从受感染的呼吸道细胞(例如,上皮细胞)中清除。我们发现 伴有呼吸道2型炎症的重症哮喘患者呼吸道上皮细胞IP表达减少。 重要的是,我们的初步数据强烈表明IP在人原代呼吸道上皮细胞中的表达 被轮状病毒(RV-A和RV-C)感染显著上调,关键IP的敲除或抑制 成分(如LMP2和LMP7)增加了呼吸道上皮病毒载量。2型细胞因子IL-13显著升高 减少RV对IP的诱导。RV感染的LMP2基因敲除小鼠(与野生型相比)无法清除病毒 有效,并增加肺部炎症。我们将验证RV期间呼吸道IP诱导的假设 感染是消除病毒感染的关键宿主防御机制,但在呼吸道中受到损害 II型炎症,导致持续感染和过度炎症。在目标1中,我们将确定 干扰素(IFN)/干扰素受体(IFNR)/STAT1轴在轮状病毒调节IP和2型炎症中的作用 在人类原代呼吸道上皮细胞中进行基因敲除实验,并使用人类的精确度- 切除暴露于IL-13、过敏原和/或轮状病毒的肺切片或基因缺陷小鼠(如IFNAR或STAT1)。在目标2中, 我们将通过IP来确定IP在RV介导的哮喘恶化中的作用和潜在的机制 缺陷小鼠(全身或呼吸道上皮条件性基因敲除)和人原代呼吸道上皮 IP基因敲除的细胞。我们将测试IP的抗病毒和抗炎功能是否依赖于其调节 RV 3C蛋白水解酶和免疫负性调节因子A20。在目标3中,我们将确定知识产权作为 2型炎症呼吸道中的抗病毒药物。通过递送单个低剂量的干扰素-L或病毒模拟物(即, PolyI:C)进入培养的人类呼吸道上皮或患有2型炎症的小鼠呼吸道,我们将测试 增强IP表达可促进呼吸道急性轮状病毒感染和炎症的消退。研究成果 将显著提高我们对宿主防御RV感染机制的理解,并可能 为治疗哮喘和其他疾病患者的轮状病毒感染提供了新的机会。
英文摘要
Project Summary/Abstract The goal of this proposal is to determine the regulation and functions of immunoproteasome (IP) during rhinovirus infection in airways with type 2 inflammation, a hallmark of the type 2 (e.g., interleukin 13 [IL-13]) high asthma. Rhinovirus (RV) infection remains a significant healthcare burden due to its contribution to exacerbations of asthma and other lung diseases. Because there is no effective therapy for airway RV infection, it is imperative to define novel mechanisms (e.g., IP) that clear RV from the infected airway cells (e.g., epithelial cells). We found reduced IP expression in airway epithelial cells of severe asthma patients with airway type 2 inflammation. Importantly, our preliminary data strongly suggest that IP expression in human primary airway epithelial cells was significantly up-regulated by RV (RV-A and RV-C) infection, and that knockout or inhibition of key IP components (e.g., LMP2 and LMP7) increased airway epithelial viral load. Type 2 cytokine IL-13 significantly reduced IP induction by RV. RV-infected LMP2 knockout (vs. wild-type) mice were unable to clear the viruses effectively, and increased lung inflammation. We will test the hypothesis that airway IP induction during RV infection serves as a critical host defense mechanism to eliminate viral infection, but is impaired in airways with type 2 inflammation, leading to persistent infection and excessive inflammation. In Aim 1, we will determine the role of the interferons (IFNs)/IFN receptor (IFNR)/STAT1 axis in IP regulation by RV and type 2 inflammation by performing gene knockout experiments in human primary airway epithelial cells, and using the human precision- cut lung slices or gene (e.g., IFNAR or STAT1) deficient mice exposed to IL-13, allergen and/or RV. In Aim 2, we will determine the role of IP in RV-mediated asthma exacerbation and underlying mechanisms by using IP deficient mice (whole body or airway epithelial conditional gene knockout) and human primary airway epithelial cells with IP gene knockout. We will test if IP’s antiviral and anti-inflammatory functions depend on its regulation of RV 3C protease and A20, a negative immune regulator. In Aim 3, we will determine the efficacy of IP as an antiviral agent in airways with type 2 inflammation. By delivering a single low-dose of IFN-l or a viral mimic (i.e., polyI:C) into cultured human airway epithelium or mouse airways with type 2 inflammation, we will test if enhancing IP expression promotes resolution of airway acute RV infection and inflammation. Research findings will significantly improve our understanding about host defense mechanisms against RV infection, and likely provide a new opportunity to treat RV infections in patients with asthma and other diseases.
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Role of immunoproteasome in airway viral infection
  • 批准号:
    10155416
  • 项目类别:
  • 资助金额:
    $56.32万
  • 财政年份:
    2020
  • 负责人:
    Hong W Chu
  • 依托单位:
Parkin in mitochondrial dysfunction and airway inflammation of obese asthma
  • 批准号:
    10264924
  • 项目类别:
  • 资助金额:
    $73.14万
  • 财政年份:
    2020
  • 负责人:
    Hong W Chu
  • 依托单位:
Parkin in mitochondrial dysfunction and airway inflammation of obese asthma
  • 批准号:
    10457989
  • 项目类别:
  • 资助金额:
    $72.92万
  • 财政年份:
    2020
  • 负责人:
    Hong W Chu
  • 依托单位:
Role of immunoproteasome in airway viral infection
  • 批准号:
    10610373
  • 项目类别:
  • 资助金额:
    $55.59万
  • 财政年份:
    2020
  • 负责人:
    Hong W Chu
  • 依托单位:
海外基金