CD39-mediated cardiovascular protection

描述（由申请人提供）：缺血性心脏病是全球主要的死亡原因。先天性心脏保护机制影响心肌对缺血再灌注的敏感性，心肌对缺血再灌注损伤敏感性的具体分子机制尚不清楚。事实上，最近召开的NHLBI保护心脏疗法翻译工作组强调了了解缺血性心脏病潜在机制的重要性，该工作组在其报告中认识到，知识的根本差距仍然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，确定了许多影响心肌对缺血性损伤易感性的变量和途径。一种这样的最近认识到的心血管保护蛋白是外核苷三磷酸二磷酸水解酶1（CD 39）。CD 39是血栓形成和心肌缺血再灌注损伤的关键介质。CD 39的过表达降低了静脉血栓形成模型中的血栓负荷，并且与野生型动物相比，CD 39的敲除导致梗死面积增加以及缺血预处理现象所提供的先天性心脏保护的丧失。因此，PI假设靶向递送CD 39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。该项目将确定CD 39在动脉血栓形成和心肌缺血/再灌注损伤中的作用，并解决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。公共卫生相关性：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）潜在机制的重要性，该工作组在其报告中认识到，知识的根本差距仍然限制了心脏保护疗法从实验到临床的有效转化。CD 39（ectonucleoside triphosphate diphosphohydrolase 1）是血栓形成和心肌缺血-再灌注损伤的重要介质。该项目将确定CD 39在动脉血栓形成和心肌缺血/再灌注损伤中的作用，并解决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。

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.