Purinergic modulation of the autoimmune vascular phenotype

自身免疫血管表型的嘌呤能调节

基本信息

  • 批准号:
    10168724
  • 负责人:
  • 金额:
    $ 15.6万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-01-01 至 2022-12-30
  • 项目状态:
    已结题

项目摘要

ABSTRACT Dead and dying cells release purine nucleotides, which engage purinergic receptors on the surfaces of leukocytes, platelets, and vascular cells to trigger inflammation, coagulation, and vasoconstriction. To counter these mediators of vascular disequilibrium, leukocytes and endothelial cells express surface ectonucleotidases (CD39 and CD73), which catalyze the step-wise phosphohydrolysis of ATP into adenosine—thereby creating an anti-inflammatory, antithrombotic “halo” around the cell. In patients with systemic lupus erythematosus (commonly referred to as “lupus”), stroke and venous thrombosis are relentlessly driven by oxidative stress and prothrombotic autoantibodies. Furthermore, our laboratory recently discovered that neutrophil extracellular traps (NETs, tangles of chromatin expelled by “NETosis”) trigger endothelial damage and in situ thrombosis in lupus. Our preliminary data now reveal that, in lupus, CD73 counteracts neutrophil infiltration, NETosis, dysfunction of the arterial endothelium, and venous thrombosis. The hypothesis driving this work is that CD73 and its downstream pathways serve as an endogenous (and potentially amplifiable) counterpoint to thrombo- inflammatory events in lupus. The Aims of this project are to: (1) Elucidate cell- and receptor-specific mechanisms by which CD73 protects against lupus-mediated dysfunction of the arterial endothelium. In addition to two traditional models of murine lupus, we will use a novel approach whereby the administration of human lupus autoantibodies into mice rapidly triggers endothelial dysfunction. Endpoints will determine the mechanism(s) by which CD73 and adenosine receptors (A2A, A2B, A3) thwart arterial inflammation and endothelial dysfunction in lupus-prone mice, and will define the extent to which lineage-specific expression of CD73 (neutrophils vs. endothelium) guards against these phenotypes. Endpoints will also globally assess the deranged autoimmune/inflammatory milieu of lupus. (2) Ascertain how CD73 and downstream purinergic signaling modulate lupus-mediated venous thrombosis. Experiments will again leverage traditional models of murine lupus, as well as a novel model whereby human lupus autoantibodies markedly potentiate venous thrombosis in mice. We will determine the extent to which lineage-specific expression of CD73 protects against venous thrombosis, and will elucidate mechanism(s) by which CD73 and adenosine receptors mitigate autoantibody-mediated NETosis. Overall, these studies should yield new insight into how a pathway that functions as an endogenous guardian against inflammation may be exploited to counteract the relentless thrombo-inflammatory course of lupus.
摘要

项目成果

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Jason Knight其他文献

Jason Knight的其他文献

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{{ truncateString('Jason Knight', 18)}}的其他基金

NETs as therapeutic targets in obstetric APS
NETs 作为产科 APS 的治疗靶点
  • 批准号:
    10786977
  • 财政年份:
    2023
  • 资助金额:
    $ 15.6万
  • 项目类别:
Scientist Training in Rheumatology Research
风湿病学研究科学家培训
  • 批准号:
    10851080
  • 财政年份:
    2023
  • 资助金额:
    $ 15.6万
  • 项目类别:
Purinergic modulation of the autoimmune vascular phenotype
自身免疫血管表型的嘌呤能调节
  • 批准号:
    10364621
  • 财政年份:
    2018
  • 资助金额:
    $ 15.6万
  • 项目类别:
Purinergic modulation of the autoimmune vascular phenotype
自身免疫血管表型的嘌呤能调节
  • 批准号:
    10581346
  • 财政年份:
    2018
  • 资助金额:
    $ 15.6万
  • 项目类别:
Innate Immunity in the Pathogenesis of Lupus and Antiphospholipid Vasculopathy
狼疮和抗磷脂血管病发病机制中的先天免疫
  • 批准号:
    9392606
  • 财政年份:
    2014
  • 资助金额:
    $ 15.6万
  • 项目类别:
Innate Immunity in the Pathogenesis of Lupus and Antiphospholipid Vasculopathy
狼疮和抗磷脂血管病发病机制中的先天免疫
  • 批准号:
    8751822
  • 财政年份:
    2014
  • 资助金额:
    $ 15.6万
  • 项目类别:
Training of Arthritis Research Scientists
关节炎研究科学家的培训
  • 批准号:
    10214517
  • 财政年份:
    1976
  • 资助金额:
    $ 15.6万
  • 项目类别:
Scientist Training in Rheumatology Research
风湿病学研究科学家培训
  • 批准号:
    10627099
  • 财政年份:
    1976
  • 资助金额:
    $ 15.6万
  • 项目类别:
Training of Arthritis Research Scientists
关节炎研究科学家的培训
  • 批准号:
    10463710
  • 财政年份:
    1976
  • 资助金额:
    $ 15.6万
  • 项目类别:

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