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CD39-mediated cardiovascular protection

CD39介导的心血管保护

基本信息

批准号：
7888321
负责人：
Richard J Gumina
金额：
$ 18.75万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-10 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7888321
关键词：
Address Adenosine Adoptive Transfer Adult Animals Area Attenuated Blood Cells Blood Platelets Blood flow Bone Marrow Bone Marrow Transplantation Cardiovascular system Carotid Artery Thrombosis Cause of Death Cells Clinical Endothelial Cells Evaluation Heart Hematopoietic Hour Human Infarction Injury Investigational Therapies Ischemia Ischemic Preconditioning Knock-out Knowledge Marrow Mediating Mediator of activation protein Metabolism Methods Modeling Molecular Monitor Morbidity - disease rate Mus Myocardial Myocardial Ischemia Myocardium National Heart, Lung, and Blood Institute P-Selectin Pathway interactions Platelet Activation Platelet aggregation Positioning Attribute Predisposition Proteins Pulmonary Thromboembolism Reperfusion Injury Reperfusion Therapy Reporting Research Risk Role Site Thrombosis Time Translations Transplantation United States Venous Venous Thrombosis Work cardiovascular injury hemodynamics in vivo insight lentiviral-mediated mortality myocardial infarct sizing overexpression promoter public health relevance research study targeted delivery tripolyphosphate working group

项目摘要

DESCRIPTION (provided by applicant): Ischemic heart disease is the leading cause of death worldwide. Innate cardioprotective mechanisms influence the susceptibility of the myocardium to ischemia-reperfusion, the specific molecular mechanisms underlying susceptibility of the myocardium to ischemia-reperfusion (I-R) injury remain unclear. Indeed, the importance of understanding the underlying mechanisms responsible for ischemic heart disease was highlighted by the recently convened NHLBI Working Group on the Translation of Therapies for Protecting the Heart which recognized in their report that fundamental gaps in knowledge remain that limit the effective translation of cardioprotective therapies from experimental to clinical settings. Our understanding of the mechanisms responsible for cardiovascular protection has expanded tremendously, identifying a number of variables and pathways that influence the susceptibility of the myocardium to ischemic damage. One such recently recognized cardiovascular protective protein is ectonucleoside triphosphate diphosphohydrolase 1 (CD39). CD39 is uniquely positioned to be a key mediator of both thrombosis and myocardial ischemia-reperfusion injury. Overexpression of CD39 decreases thrombotic burden in a model of venous thrombosis and knockout of CD39 results in an increased infarct size in comparison to wild-type animals as well as loss of the innate cardioprotection afforded by the phenomenon of ischemic preconditioning. Therefore, the PI hypothesizes that targeted delivery of CD39 to sites of cardiovascular injury will attenuate in vivo arterial thrombosis and reduce myocardial ischemia/reperfusion injury. This project will define the role of CD39 in arterial thrombosis and myocardial ischemia/reperfusion injury and address whether targeted delivery of a cardiovascular protective protein via platelet-specific expression can reduce arterial thrombosis and myocardial ischemia-reperfusion injury. PUBLIC HEALTH RELEVANCE: The importance of understanding the underlying mechanisms responsible for ischemic heart disease, a leading cause of morbidity and mortality in the United States, was highlighted by the recently convened NHLBI Working Group on the Translation of Therapies for Protecting the Heart which recognized in their report that fundamental gaps in knowledge remain that limit the effective translation of cardioprotective therapies from experimental to clinical settings. CD39 (ectonucleoside triphosphate diphosphohydrolase 1) is uniquely positioned to be a key mediator of both thrombosis and myocardial ischemia-reperfusion injury. This project will define the role of CD39 in arterial thrombosis and myocardial ischemia/reperfusion injury and address whether targeted delivery of a cardiovascular protective protein via platelet-specific expression can reduce arterial thrombosis and myocardial ischemia-reperfusion injury.

描述（由申请人提供）：缺血性心脏病是全世界死亡的主要原因。先天性心脏保护机制影响心肌缺血再灌注的易感性，但心肌缺血再灌注（I-R）损伤易感性的具体分子机制仍不清楚。事实上，最近召开的 NHLBI 保护心脏疗法转化工作组强调了了解导致缺血性心脏病的根本机制的重要性，该工作组在报告中认识到，知识方面的根本差距仍然存在，限制了心脏保护疗法从实验到临床的有效转化。我们对心血管保护机制的理解已经大大扩展，确定了影响心肌缺血损伤易感性的许多变量和途径。最近公认的一种心血管保护蛋白是外核苷三磷酸二磷酸水解酶 1 (CD39)。 CD39 具有独特的地位，是血栓形成和心肌缺血再灌注损伤的关键介质。 CD39 的过表达可降低静脉血栓形成模型中的血栓形成负担，与野生型动物相比，CD39 的敲除会导致梗死面积增加，并导致缺血预处理现象所提供的先天心脏保护作用丧失。因此，PI假设将CD39靶向递送至心血管损伤部位将减弱体内动脉血栓形成并减少心肌缺血/再灌注损伤。该项目将明确 CD39 在动脉血栓形成和心肌缺血/再灌注损伤中的作用，并探讨通过血小板特异性表达靶向递送心血管保护蛋白是否可以减少动脉血栓形成和心肌缺血/再灌注损伤。公共健康相关性：最近召开的 NHLBI 保护心脏疗法转化工作组强调了了解缺血性心脏病（美国发病率和死亡率的主要原因）的根本机制的重要性，该工作组在报告中认识到，知识方面仍然存在根本性差距，限制了心脏保护疗法从实验到临床的有效转化。 CD39（外核苷三磷酸二磷酸水解酶 1）具有独特的地位，是血栓形成和心肌缺血再灌注损伤的关键介质。该项目将明确 CD39 在动脉血栓形成和心肌缺血/再灌注损伤中的作用，并探讨通过血小板特异性表达靶向递送心血管保护蛋白是否可以减少动脉血栓形成和心肌缺血/再灌注损伤。