Purinergic regulation of Innate Immunity to promote Venous Homeostasis

先天免疫的嘌呤能调节促进静脉稳态

• 批准号: 10382231
• 负责人: David J. Pinsky
• 金额: $ 42.9万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-05 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10382231
• 关键词: Affect; American; Autocrine Communication; Automobile Driving; Blood Cells; Blood Circulation; Blood Platelets; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Adhesion Molecules; Cell Lineage; Cells; Cessation of life; Chromatin; Clinical Trials; Coagulation Process; Complication; Data; Deep Vein Thrombosis; Defense Mechanisms; Deposition; Development; Disease; Electron Microscopy; Endothelium; Environment; Enzymes; Erythrocytes; Feedback; Fiber; Fibrin; Generations; Genes; Glycocalyx; Goals; Homeostasis; Hydrolysis; Immune; In Vitro; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Interleukin-1 beta; Interruption; Kinetics; Lead; Leg; Leukocytes; Mediating; Modeling; Molecular; Mus; Myelogenous; Myeloid Cells; Natural Immunity; Neurofibrillary Tangles; Nucleotides; Paracrine Communication; Phenotype; Platelet aggregation; Process; Pulmonary Embolism; Regulation; Role; Signal Transduction; Structure; Surface; Testing; Therapeutic; Thrombin; Thrombosis; Thrombus; United States; Venous; Venous Thrombosis; Work; arm; cytokine; deep vein; experimental study; extracellular; immune activation; improved; in vivo; injured; insight; leukocyte activation; macrophage; microvesicles; mouse model; neutrophil; phosphodiester; recruit; response; thrombogenesis; thromboinflammation; thrombotic; venous thromboembolism

ABSTRACT Deep venous thrombosis (DVT) and secondary pulmonary embolism (together, VTE) affect 900,000 Americans, and result in >60,000 deaths each year. A growing body of evidence supports the concept of crosstalk between inflammation and coagulation which amplifies the thrombo-inflammatory response in VTE. Activated, injured, and dying cells release nucleotides that form purinergic halo of “danger” signals that disrupt vascular homeostasis. Located on the surface of leukocytes and the endothelium, the vascular ectonucleotidase, CD39 rapidly phosphohydrolyzes ATP, and ADP to extinguish these “danger” signals and promote homeostasis. We have found that CD39 is a potent suppressor of the thrombo-inflammatory response in DVT. Our new preliminary data show that CD39 inhibits circulating leukocyte-platelet interactions, and restricts activation of programmed innate immune responses, including inflammasome assembly and neutrophil extracellular trap (NET) formation, key drivers of the growing thrombus. The hypothesis driving this work is that CD39 provides a critical vascular checkpoint at the intersection of innate immunity and thrombosis to arrest the relentless venous thrombo-inflammatory cycle. Using unique cell lineage (myeloid, neutrophil, endothelial)-specific CD39 gene-deleted mice we have generated, and complementary models of DVT, we will: 1) Elucidate the role for CD39 on cellular recruitment during venous thrombogenesis and maturation. These experiments will define the effect of lineage-specific CD39 on blood cell recruitment, and the spatial dynamics of their interactions during venous thrombogenesis; 2) Determine the mechanism(s) by which myeloid CD39 protects against venous thrombo-inflammation. These experiments will determine the contributions of macrophage and neutrophil CD39 to venous thrombosis. Complementary in vitro and in vivo studies with genetically-modified mice will elucidate the molecular signaling processes by which CD39 inhibits inflammasome activation during thrombogenesis; 3) Determine the effect of CD39-deficiency on microvesicle phenotype, function, and kinetics, during venous thrombosis. These studies will reveal the functional consequences of altering global- and lineage-specific CD39 on microvesicle-mediated thrombo-inflammatory signaling. These studies should yield new insights into how an ectonucleotidase that functions as a checkpoint at the intersection of thrombosis and inflammation may be exploited to improve treatments in venous thrombosis.

抽象的 深静脉血栓形成（DVT）和次级肺栓塞（一起）影响900,000 美国人，每年导致60,000人死亡。越来越多的证据支持 炎症和凝结之间的串扰，这放大了VTE中的血栓炎症反应。 激活，受伤和垂死的细胞释放形成“危险”信号的嘌呤能光环的核苷酸 血管稳态。血管位于白细胞和内皮的表面 副核苷酸酶，CD39迅速磷酸氢化液ATP，ADP扑灭了这些“危险”信号和 促进安装。我们发现CD39是血栓炎性反应的潜在抑制剂 在DVT中。我们的新初步数据表明，CD39抑制了循环的白细胞 - 血小板相互作用，并且 限制激活编程的先天免疫反应，包括炎症体组装和 中性粒细胞外陷阱（净）形成，生长血栓的关键驱动因素。驱动这一假设 工作是CD39在先天免疫和血栓形成的交点上提供了关键的血管检查点 阻止无情的静脉血栓炎性周期。使用独特的细胞谱系（髓样，中性粒细胞， 内皮） - 我们已经生成的特异性CD39基因删除的小鼠，以及DVT的互补模型，我们将： 1）在静脉血栓形成和成熟过程中阐明CD39在细胞募集中的作用。这些 实验将定义谱系特异性CD39对血细胞募集的影响和空间动力学 它们在静脉血栓形成过程中的相互作用； 2）确定髓样CD39的机制 预防静脉血管症。这些实验将确定 巨噬细胞和中性粒细胞CD39到静脉血栓形成。互补的体外和体内研究 遗传改性的小鼠将阐明CD39抑制的分子信号传导过程 血栓形成期间的炎性体激活； 3）确定CD39缺乏对微丝的影响 静脉血栓形成期间的表型，功能和动力学。这些研究将揭示功能 改变全球和谱系特异性CD39对微丝介导的血栓炎症的后果 信号。这些研究应产生新的见识 可以探索血栓形成和感染的交集，以改善静脉的治疗 血栓形成。