CD39-mediated cardiovascular protection

CD39介导的心血管保护

• 批准号: 7740404
• 负责人: Richard J Gumina
• 金额: $ 22.5万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-10 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7740404
• 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; 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

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）：缺血性心脏病是全球死亡的主要原因。先天心脏保护机制会影响心肌对缺血再灌注的敏感性，这是心肌对缺血 - 灌注灌注（I-R）损伤的特定分子机制尚不清楚。的确，最近召集的NHLBI工作组强调了理解负责缺血性心脏病的基本机制的重要性，以保护疗法的翻译，以保护心脏，这些疗法在其报告中认识到知识的基本差距仍然限制了从实验到临床环境实验的心脏保护疗法的有效翻译。我们对负责心血管保护的机制的理解已大大扩展，确定了许多变量和途径，这些变量和途径影响了心肌对缺血性损害的敏感性。最近识别的一种这种心血管保护蛋白是三磷酸二磷酸二磷酸二磷酸酶1（CD39）。 CD39的独特位置是血栓形成和心肌缺血 - 再灌注损伤的关键介体。与野生型动物相比，CD39的过表达减轻了静脉血栓形成和CD39敲除的模型中的血栓负担，并减轻了梗塞大小的增加，以及缺血性预处理现象所提供的先天心脏保护。因此，PI假设将CD39的目标递送到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。该项目将定义CD39在动脉血栓形成和心肌缺血/再灌注损伤中的作用，并通过血小板特异性表达来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：了解美国发病率和死亡率的主要原因的基本机制的重要性，这是美国发病率和死亡率的主要原因，最近召集的NHLBI NHLBI工作组强调了有关保护心脏的疗法的工作组，该疗法在他们的报告中认识到，在其报告中，在知识上仍然有效地转化了Cardiection Cardiextions的基本差距。 CD39（Ectonucleoside triphosphate diphosphohydrollase 1）独特地定位为血栓形成和心肌缺血 - 再灌注损伤的关键介体。该项目将定义CD39在动脉血栓形成和心肌缺血/再灌注损伤中的作用，并通过血小板特异性表达来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。