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

基本信息

批准号：
7179030
负责人：
David J. Pinsky
金额：
$ 36.46万
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：
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/7179030
关键词：
5&apos -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&apos -5&apos )cytidine-3&apos -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

项目摘要

DESCRIPTION (provided by applicant): 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 pathogenesis 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.

描述（由申请人提供）：激活的血小板释放的 ADP 会募集附近的血小板，导致血栓病灶爆炸性积聚。活化的血小板或受损细胞释放的 ATP 会促进炎症。通过外切核苷酸酶 CD39（核苷酸二磷酸水解酶 1，转化 ATP？ADP？AMP）和 CD73（51 核苷酸酶，转化 AMP？腺苷）的连续作用，细胞外核苷酸的协调磷酸水解是限制血栓形成和炎症的重要内皮稳态机制在血管界面处。 CD39基因缺失小鼠在局灶性脑缺血的情况下表现出潜在的血栓前表型，并且结果比对照组更差。这些小鼠可以通过重组可溶性 CD39 来拯救，该 CD39 保留了腺苷三磷酸双磷酸酶活性，且不会增加脑内出血。此外，高胆固醇血症的 ApoE/CD39 双敲除小鼠表现出过度的动脉粥样硬化形成，这与血小板和炎症细胞募集到正在形成的斑块中的作用一致。这些数据表明核酸外切酶可以预防动脉粥样硬化血栓事件，并且与中风的发病机制相关。实验将阐明 CD39 和 CD73 的动脉粥样硬化保护机制，重点关注它们抑制血小板活化和炎症级联的能力，使用野生型、cd39 或 cd73 基因缺失小鼠在对照或高胆固醇血症背景下进行。实验将使用 solCD39（和/或纯化的 CD73）作为单一疗法或作为低剂量溶栓疗法的辅助疗法，测试核酸外切酶是否可以改善易发生动脉粥样硬化的脑血管环境中的缺血性中风结果。这里的首要目标是描绘一个保护血管免受动脉粥样硬化血栓形成的内源性级联，并确定它是否可以在治疗上用于改善缺血性中风结果。与公共健康的相关性：该项目将探讨血管内壁细胞上存在的两种蛋白质如何降解循环物质，否则这些物质会促进凝血、炎症和动脉粥样硬化。利用这些蛋白质的活性可能会带来一种预防血栓形成和动脉粥样硬化的新方法，从而带来一种全新的、也许更安全的中风治疗方法。