Ectonucleotidases in Atherothrombosis and Stroke

外切核苷酸酶在动脉粥样硬化血栓形成和中风中的作用

• 批准号: 7341621
• 负责人: David J. Pinsky
• 金额: $ 36.41万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-19 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7341621
• 关键词: 5' -Nucleotidase; Abbreviations; Accounting; Adam11 gene; Adenosine; Adenosine Diphosphate; Adenosine Triphosphate; Adhesions; Alteplase; American; Anti-Inflammatory Agents; Anti-inflammatory; Apolipoprotein E; Apyrase; Atherosclerosis; Automobile Driving; Blood; Blood Platelets; Blood Vessels; Brain; Breeding; CCL17 gene; CCL22 gene; Catalytic Domain; Cell Adhesion Molecules; Cell Communication; Cell Line; Cells; Cerebral Ischemia; Cerebral hemisphere hemorrhage; Cerebrovascular Circulation; Cerebrum; Chemokine, Other; Chloride Ion; Chlorides; Coagulants; Coagulation Process; Core-Binding Factor; Data; Deposition; Dose; Endothelial Cells; Endothelium; Engineering; Environment; Event; Exhibits; Factor VIII-Related Antigen; Fibrinolytic Agents; Genes; Genetic; Glossary; Goals; Hour; In Vitro; Infarction; Inflammation; Inflammatory; Injury; Integrins; Intercellular adhesion molecule 1; Ischemic Stroke; Knockout Mice; Lead; Leukocytes; Lipids; Mediating; Metabolism; Middle Cerebral Artery Occlusion; Mus; Nucleotidases; Nucleotides; Outcome; Pathogenesis; Pathologic; Peptides; Phenotype; Platelet Activation; Platelet Factor 4; Platelet Glycoproteins; Property; Proteins; Public Health; RANTES; Reaction; Recombinants; Recruitment Activity; Relative (related person); Research Personnel; Risk; Role; Site; Small Inducible Cytokine A18; SolCD39; Stroke; Stroke prevention; Stromal Cell-Derived Factor 1; Supplementation; Symptoms; Testing; Therapeutic; Thrombin; Thrombolytic Therapy; Thrombosis; Treatment Efficacy; VWF gene; Vascular Cell Adhesion Molecule-1; adenosine monophosphatase; adenylyl(3' -5' )cytidine-3' -phosphate; atherogenesis; atheroprotective; atherothrombosis; carbene; cerebrovascular; chemokine; chlorambucil/dactinomycin/methotrexate protocol; extracellular; human CCL17 protein; improved; inhibitor/antagonist; injured; macrophage-derived chemokine; middle cerebral artery; migration; monocyte; neutrophil; novel therapeutics; nucleotidase; prevent; programs; research study; therapeutic target; thrombolysis; trafficking; triphenyltetrazolium; von Willebrand Factor

ADP released from activated platelets recruits nearby platelets, resulting in explosive accretion of a thrombotic nidus. ATP, released from activated platelets or injured cells, promotes inflammation. The coordinated phosphohydrolysis of extracellular nucleotides, by the sequential actions of the ectonucleotidases CD39 (nucleotide diphosphohydrolase 1, converts ATP-> ADP->AMP) and CD73 (51 nucleotidase, converts AMP->adenosine), is an important endothelial homeostatic mechanism which limits thrombosis and inflammation at the blood-vessel interface. CD39 gene null mice exhibit a latent prothrombotic phenotype and worse outcomes than controls in the setting of focal cerebral ischemia. These mice can be rescued by recombinant soluble CD39, which retains apyrase activity, without increasing intracerebral hemorrhage. Furthermore, hypercholesterolemic ApoE/CD39 double knockout mice exhibit exaggerated atherogenesis, consistent with a role for platelet and inflammatory cell recruitment into the developing plaque. These data suggest that ectonucleotidases protect against atherothrombotic events and are relevant to the pathoaenesis of stroke. Experiments will elucidate mechanisms by which CD39 and CD73 are atheroprotective, focusing on their ability to suppress platelet activation and inflammatory cascades, using wild-type, cd39- or cd73-gene null mice in control or hypercholesterolemic backgrounds. Experiments will test whether ectonucleotidases improve ischemic stroke outcomes in an atherosclerosis-prone cerebrovascular milieu, using solCD39 (and/or purified CD73) as monotherapy or as an adjunct to low dose thrombolytic therapy. The overarching goal here is to delineate an endogenous cascade which protects vessels against atherothrombosis, and determine whether it may be therapeutically harnessed to ameliorate ischemic stroke outcomes. Relevance to Public Health: This project will explore how two proteins, which exist on cells lining blood vessels, degrade circulating substances which would otherwise promote clotting, inflammation, and atherosclerosis. Harnessing the activity of these proteins might lead to a new way of preventing clot formation and atherosclerosis, and thereby lead to a completely new and perhaps safer treatment for stroke.

从激活的血小板新兵释放的ADP附近血小板，导致爆炸性 血栓形成nidus的积聚。从活化的血小板或受伤的细胞释放的ATP促进 炎。通过顺序的细胞外核苷酸协调的磷酸化水解析 邻核酶CD39（核苷酸双磷酸化酶1，转化ATP->）的作用 ADP-> AMP）和CD73（51个核苷酸酶，转化AMP->腺苷），是重要的内皮 稳态机制限制了血管界面处的血栓形成和炎症。 CD39基因null小鼠表现出比对照组表现出潜在 局灶性脑缺血的设置。这些小鼠可以通过重组可溶性CD39营救 保留呼吸酶活性，而不会增加脑出血。此外， 高胆固醇APOE/CD39双基因敲除小鼠表现出夸张的动脉粥样硬化， 与血小板和炎症细胞募集到发育中的斑块中的作用一致。 这些数据表明，邻核酶酶可以预防动脉粥样硬化事件，并且是 与中风的病原体有关。实验将阐明CD39和CD39和 CD73具有动脉保护性，重点是抑制血小板激活和炎症的能力 使用野生型，CD39或CD73-GENE NULL小鼠对照或高胆固醇血症的级联 背景。实验将测试胚核苷酸酶是否改善缺血性卒中结果 在动脉粥样硬化的脑血管脑血管环境中，使用SOLCD39（和/或纯化的CD73）作为 单一疗法或低剂量溶栓疗法的辅助。这里的总体目标是 描述一个内源性级联反应，可保护血管免受动脉粥样硬化的影响，并确定 是否可以利用治疗方法来改善缺血性中风结果。 与公共卫生的相关性：该项目将探讨细胞衬里存在的两种蛋白质 血管，降解循环的物质，否则会促进凝结， 炎症和动脉粥样硬化。利用这些蛋白质的活性可能导致新的 防止凝块形成和动脉粥样硬化的方法，从而导致一个全新的和 也许对中风更安全。