MICA: Myeloperoxidase inhibition as a potential therapy in anti-neutrophil cytoplasmic antibody vasculitis

MICA:髓过氧化物酶抑制作为抗中性粒细胞胞质抗体血管炎的潜在疗法

基本信息

  • 批准号:
    MR/R004870/1
  • 负责人:
  • 金额:
    $ 50.53万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2018
  • 资助国家:
    英国
  • 起止时间:
    2018 至 无数据
  • 项目状态:
    已结题

项目摘要

Antibodies are circulating proteins in the immune system that normally fight infection. The immune system can malfunction and in some patients antibodies stick to white blood cells and cause a form of vasculitis or blood vessel inflammation. This can affect joints, lungs, kidneys, skin and other tissues and occurs most often in older adults. The antibodies bind in particular to the proteins myeloperoxidase (MPO) proteinase 3 which are found in certain white blood cells. The antibodies are thought to play a key role in causing disease. MPO is a protein in white blood cells that normally fights infection and can also cause tissue inflammation in certain diseases. Thus blocking MPO may be beneficial in inflammatory disease such as vasculitis. The proposed study will define whether the MPO inhibitor AZD5904 is effective in reducing disease onset and/or development, and elucidate potential mechanisms. Our hypothesis is that inhibition of MPO enyzme activity will be an effective therapy for vasculitis. Using the MPO inhibitor AZD5904, we plan to test this through a combination of experiments using human and murine white blood cells in vitro and murine in vivo models. In the first part of the research, we will use an in vivo model of anti-MPO vasculitis in mice. In addition to examining the therapeutic efficacy of AZD5904 we will explore the mechanisms of this effect with particular reference to the same type of white blood cell that will be studied in the in vitro work with patient samples. We will also aim to understand the effect of anti-MPO antibody, purified from the blood of patients with vasculitis, on human white blood cells. Our preliminary data suggest important effects on the responses of a particular type of white blood cell that are relevant to disease. We aim to understand the mechanism by which these effects depend on MPO enzyme, and to link this to potential consequences for disease expression in the murine model. This will place us in an ideal position to proceed to clinical trials and this would naturally follow from the plan of work contained in the current application.
抗体是免疫系统中的循环蛋白质,通常用于对抗感染。免疫系统可能发生故障,在一些患者中,抗体粘附在白色血细胞上,导致血管炎或血管炎症。这可能会影响关节,肺,肾脏,皮肤和其他组织,最常发生在老年人身上。抗体特别结合在某些白色血细胞中发现的蛋白质髓过氧化物酶(MPO)蛋白酶3。这些抗体被认为在引起疾病方面起着关键作用。MPO是白色血细胞中的一种蛋白质,通常可以对抗感染,也可以在某些疾病中引起组织炎症。因此,阻断MPO可能对炎症性疾病如血管炎有益。这项研究将确定MPO抑制剂AZD 5904是否能有效减少疾病的发生和/或发展,并阐明潜在的机制。我们的假设是,抑制MPO酶活性将是一种有效的治疗血管炎。使用MPO抑制剂AZD 5904,我们计划通过使用人和小鼠白色血细胞的体外实验和小鼠体内模型的组合实验来测试这一点。在研究的第一部分中,我们将使用小鼠体内抗MPO血管炎模型。除了检查AZD 5904的治疗效果外,我们还将探索这种作用的机制,特别是参考将在体外工作中使用患者样本研究的相同类型的白色血细胞。我们还将了解从血管炎患者血液中纯化的抗MPO抗体对人白色血细胞的影响。我们的初步数据表明,对与疾病相关的特定类型的白色血细胞的反应有重要影响。我们的目的是了解这些作用依赖于MPO酶的机制,并将其与小鼠模型中疾病表达的潜在后果联系起来。这将使我们处于进行临床试验的理想位置,这将自然遵循当前申请中包含的工作计划。

项目成果

期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Antimyeloperoxidase antibodies modulate inflammatory responses and activate profibrotic pathways in human monocytes.
  • DOI:
    10.1016/j.jaut.2023.103060
  • 发表时间:
    2023-09
  • 期刊:
  • 影响因子:
    12.8
  • 作者:
    Florez-Barros, Fernanda;Bearder, Siobhan;Pavlidis, Polychronis;Robson, Michael G.
  • 通讯作者:
    Robson, Michael G.
Myeloid expression of the anti-apoptotic protein Mcl1 is required in anti-myeloperoxidase vasculitis but myeloperoxidase inhibition is not protective.
  • DOI:
    10.1016/j.kint.2022.08.028
  • 发表时间:
    2023-01
  • 期刊:
  • 影响因子:
    19.6
  • 作者:
    Florez-Barros, Fernanda;Bearder, Siobhan;Kull, Bengt;Freeman, Adrian;Mocsai, Attila;Robson, Michael G.
  • 通讯作者:
    Robson, Michael G.
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Michael Robson其他文献

856: Verifying a previously described classification system for intrapartum cesarean delivery in a national Norwegian study
  • DOI:
    10.1016/j.ajog.2019.11.870
  • 发表时间:
    2020-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Joerg Kessler;Michael Robson
  • 通讯作者:
    Michael Robson
420 CS in Single Cephalic Term Nulliparas: The Changing Size of Robson Group 1 and 2
  • DOI:
    10.1016/j.ajog.2023.11.446
  • 发表时间:
    2024-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Gillian Corbett;Kim Ryan;Anne Twomey;Nicola O. Riordan;Declan Keane;Michael Robson
  • 通讯作者:
    Michael Robson
840 How Much Oxytocin Do We Give? Cumulative Doses for Labour Acceleration
  • DOI:
    10.1016/j.ajog.2023.11.864
  • 发表时间:
    2024-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Nicola O. Riordan;Michael Robson;Declan Keane
  • 通讯作者:
    Declan Keane
413: Classification of intrapartum cesarean delivery: a starting point for more detailed analysis
  • DOI:
    10.1016/j.ajog.2016.11.671
  • 发表时间:
    2017-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Sarah Campbell;Martina Murphy;Declan P. Keane;Michael Robson
  • 通讯作者:
    Michael Robson
586: Classification of cesarean delivery rates, 10 Robson groups over 10 years: what have we learned?
  • DOI:
    10.1016/j.ajog.2016.11.320
  • 发表时间:
    2017-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    David A. Crosby;Martina Murphy;Ricardo Segurado;Fionnuala Byrne;Rhona Mahony;Michael Robson;Fionnuala M. McAuliffe
  • 通讯作者:
    Fionnuala M. McAuliffe

Michael Robson的其他文献

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