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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：
Jason Knight
金额：
$ 15.6万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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

来源：
https://reporter.nih.gov/project-details/10168724
关键词：
Adenosine Agonist Anti-Inflammatory Agents Antiphospholipid Antibodies Atherosclerosis Autoantibodies Autoimmune Diseases Autoimmune Process Automobile Driving Blood Platelets Blood Vessels Blood coagulation Bone Marrow Cells Cessation of life Chromatin Clinical Coagulation Process Data Disease Endothelial Cells Endothelium Enzymes Event Fibrinolytic Agents Functional disorder Genetic Models Goals Human Hydrocarbons In Situ In Vitro Inflammation Intervention Knock-out Laboratories Leukocytes Lupus Mediating Mediator of activation protein Minority Modeling Mus Myocardial Infarction Neurofibrillary Tangles Neutrophil Activation Neutrophil Infiltration Oxidative Stress Pathway interactions Patients Phenotype Pristane Purine Nucleotides Purinergic P1 Receptors Purinoceptor Relaxation Respiratory Burst Signal Pathway Signal Transduction Stroke Surface Systemic Lupus Erythematosus Therapeutic Thrombosis Thrombus Tissues Venous Venous Thrombosis Wild Type Mouse Woman Work differential expression endothelial dysfunction experience experimental study extracellular inflammatory milieu insight lupus prone mice mouse model neutrophil novel novel strategies prevent receptor reconstitution targeted treatment thromboinflammation vasoconstriction

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