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.

从活化的血小板释放的ADP招募附近的血小板，导致爆炸性的 血栓形成病灶的增加。从活化的血小板或受损细胞中释放的ATP， 炎症细胞外核苷酸的协调磷酸化水解，通过连续的 外核苷酸酶CD 39（核苷酸二磷酸水解酶1，将ATP-> ADP->AMP）和CD 73（51核苷酸酶，转化AMP->腺苷），是重要的内皮细胞 在血管界面限制血栓形成和炎症的稳态机制。 CD 39基因敲除小鼠表现出潜在的血栓形成前表型和比对照组更差的结果， 局灶性脑缺血的设置。这些小鼠可以通过重组可溶性CD 39， 其保留腺苷三磷酸双磷酸酶活性而不增加脑内出血。此外，委员会认为， 高胆固醇血症ApoE/CD 39双敲除小鼠表现出过度的动脉粥样硬化形成， 这与血小板和炎性细胞募集到发展中的斑块中的作用一致。 这些数据表明，外核苷酸酶保护动脉粥样硬化血栓形成事件， 与中风的病理过程有关。实验将阐明CD 39和 CD 73是动脉粥样硬化保护性的，集中在它们抑制血小板活化和炎症反应的能力上。 级联反应，使用野生型，CD 39-或CD 73-基因缺失小鼠在对照或高胆固醇血症 背景实验将测试外核苷酸酶是否改善缺血性中风的结果 在动脉粥样硬化倾向的脑血管环境中，使用solCD 39（和/或纯化的CD 73）作为 单药治疗或作为低剂量溶栓治疗的辅助治疗。这里的首要目标是 描述一种保护血管免受动脉粥样硬化血栓形成的内源性级联反应，并确定 是否可以在治疗上利用它来改善缺血性中风的结果。 与公共卫生的相关性：该项目将探索存在于细胞内衬中的两种蛋白质 血管，降解循环物质，否则会促进凝血， 炎症和动脉粥样硬化。利用这些蛋白质的活性可能会导致一种新的 预防血栓形成和动脉粥样硬化的方法，从而导致一个全新的， 也许是治疗中风更安全的方法