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Platelets in vascular injury repair

血小板在血管损伤修复中的作用

基本信息

批准号：
10328958
负责人：
JOHN HWA
金额：
$ 56.39万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-15 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10328958
关键词：
Address Affect Angioplasty Antiplatelet Drugs Apoptosis Arterial Injury Aspirin Autopsy Biometry Blood Platelets Blood Vessels Bypass Cardiovascular Diseases Cardiovascular system Cell Communication Cell Proliferation Cellular biology Complex Devices Diabetes Mellitus Diabetic mouse Disease Doctor of Philosophy Dose Endocytosis Endothelium Equilibrium Event Exhibits Exposure to Hemostatic function Human Hyperplasia In Vitro Inflammation Injury Intervention Literature Mediating Mediator of activation protein MicroRNAs Mus Operative Surgical Procedures Patients Pharmaceutical Preparations Phenotype Platelet Activation Platelet-Derived Growth Factor Play Positioning Attribute Procedures Process Proliferating Prostaglandins I Recovery Regulation Reporter Resolution Role Sampling Secondary Prevention Site Smooth Muscle Myocytes Stents Thrombosis Thromboxanes Trauma Vascular Smooth Muscle base cell dedifferentiation cell type diabetic diabetic patient experience genome-wide in vivo inhibitor injury and repair insight miRNA expression profiling mouse model new therapeutic target novel prevent programs repaired restenosis therapeutic target uptake vascular injury

项目摘要

PROJECT SUMMARY/ABSTRACT Percutaneous arterial interventions and arterial bypass surgeries are complicated by the problem of intimal hyperplasia (restenosis). Diabetic patients are more likely to experience restenosis, even after drug-eluting stents. With ever increasing numbers of intravascular (e.g. angioplasty and insertion of devices) and surgical procedures (e.g. bypass) for highly prevalent cardiovascular diseases, optimal resolution of repair is essential. The process of arterial repair after injury is complex. Initiation of repair after injury is well studied with thrombosis followed by inflammation, cellular proliferation and remodeling. Resolution of the repair process is poorly understood, particularly, what constitutes the “brake” to prevent excessive repair? Platelets provide a first and crucial line of defense against vascular injury, initially maintaining hemostasis. Upon activation, platelets also release bioactive mediators such as PDGF and thromboxane, promoting VSMC dedifferentiation from a quiescent contractile phenotype to a highly synthetic and proliferating cell type, promoting injury repair. Excessive repair, such as observed with intimal hyperplasia in diabetes mellitus (DM) after surgical or vascular interventions, can result from enhanced VSMC dedifferentiation and proliferation. We will address the hypothesis that horizontal transfer of platelet-derived miRNAs into VSMCs provide a novel mechanism for regulating VSMC phenotypic switching, preventing excessive repair and intimal hyperplasia. We are in a unique position to address our hypothesis with recognized surgical expertise in vascular surgical interventions and VSMC biology (Alan Dardik MD and Kathleen Martin PhD), platelet expertise (John Hwa MD PhD, Wai Ho Tang PhD), and diabetes mellitus (Silvio Inzucchi MD, Raimund Herzog MD). In the short term we will have presented a novel mechanism for platelet-VSMC interaction and arterial injury repair. In the long term, these mechanistic insights may provide new therapeutic targets in promoting arterial injury repair.

项目概要/摘要经皮动脉介入治疗和动脉搭桥手术因内膜问题而变得复杂增生（再狭窄）。糖尿病患者更容易出现再狭窄，即使在药物洗脱后也是如此支架。随着血管内手术（例如血管成形术和装置插入）数量的不断增加针对高度流行的心血管疾病的外科手术（例如搭桥手术），最佳修复分辨率是必不可少的。动脉损伤后的修复过程是复杂的。损伤后开始修复效果良好研究了血栓形成以及随后的炎症、细胞增殖和重塑。决议人们对修复过程知之甚少，特别是什么构成了防止过度修复的“刹车”？血小板提供了抵御血管损伤的第一道也是至关重要的防线，最初是维持止血。激活后，血小板还释放生物活性介质，如 PDGF 和血栓素，促进 VSMC 从静止收缩表型去分化为高度合成和增殖的细胞型，促进损伤修复。过度修复，例如在糖尿病中观察到的内膜增生手术或血管干预后的糖尿病 (DM)，可能是由于 VSMC 去分化增强和增殖。我们将讨论血小板衍生的 miRNA 水平转移至 VSMC 的假设提供一种调节 VSMC 表型转换、防止过度修复和内膜增生。我们处于独特的地位，可以通过公认的外科手术来解决我们的假设血管外科干预和 VSMC 生物学方面的专业知识（Alan Dardik 医学博士和 Kathleen Martin 博士），血小板专业知识（John Hwa MD 博士、Wai Ho Tang 博士）和糖尿病（Silvio Inzucchi 医学博士、雷蒙德·赫尔佐格医学博士）。短期内我们将提出一种血小板-VSMC 的新机制相互作用和动脉损伤修复。从长远来看，这些机制见解可能会提供新的促进动脉损伤修复的治疗目标。