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：
10364621
负责人：
Jason Knight
金额：
$ 56.76万
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/10364621
关键词：
Adenosine Agonist Anti-Inflammatory Agents Antiphospholipid Antibodies Atherosclerosis Autoantibodies Autoimmune Autoimmune Diseases 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 thrombotic 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.

抽象的死亡和垂死的细胞释放嘌呤核苷酸，它们在表面上接合嘌呤能受体白细胞，血小板和血管细胞引发注射，凝结和血管收缩。对抗这些血管二动介质，白细胞和内皮细胞表达表面乙核苷酸酶（CD39和CD73），将ATP的逐步磷酸化水解析成腺苷细胞周围的抗炎，抗血栓形成的“光晕”。全身性红斑狼疮的患者（通常称为“狼疮”），中风和静脉血栓形成是由氧化应激驱动的和促血栓性自身抗体。此外，我们的实验室最近发现中性粒细胞外细胞外陷阱（网状，染色质缠结，被“ Netosis”驱除）触发内皮损害和原位血栓形成狼疮。我们的初步数据现在表明，在狼疮中，CD73抵消了中性粒细胞的浸润，Netosis，动脉内皮和静脉血栓形成的功能障碍。推动这项工作的假设是CD73 它的下游途径是Thrombo- 狼疮中的炎症事件。该项目的目的是：（1）阐明CD73保护的细胞和接收器特异性机制反对狼疮介导的动脉内皮功能障碍。除了两种传统的鼠模型狼疮，我们将使用一种新颖的方法，将人类狼疮自身抗体施用到小鼠中迅速触发内皮功能障碍。端点将确定CD73和CD73和腺苷受体（A2A，A2B，A3）阻止动脉注射和狼疮可容纳小鼠的内皮功能障碍，并将定义CD73（中性粒细胞与内皮）守卫的谱系特异性表达的程度反对这些表型。终点还将在全球范围内评估危险的自身免疫/炎症环境狼疮。（2）确定CD73和下游嘌呤能信号如何调节狼疮介导的静脉血栓形成。实验将再次利用鼠狼疮的传统模型以及一种新型模型人狼疮自身抗体显着潜在的小鼠静脉血栓形成。我们将确定 CD73的谱系特异性表达在多大程度上预防静脉血栓形成，并将阐明 CD73和腺苷受体减轻自身抗体介导的Netosis的机制。总体而言，这些研究应该对充当内源性监护人的途径如何产生新的见解可以探索反对炎症，以抵消狼疮的无端血栓炎性过程。