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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：
10560637
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 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10560637
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 Coculture Techniques Complex Devices Diabetes Mellitus Diabetic mouse Disease Doctor of Philosophy Dose Endocytosis Endothelium Equilibrium Event Exhibits Exposure to Femur Hemostatic function Human Hyperplasia In Vitro Inflammation Injury Intervention Literature Mediating Mediator 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 Surgical complication Thrombosis Thromboxanes Trauma Vascular Smooth Muscle 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.

项目总结/摘要经皮动脉介入术和动脉旁路手术由于内膜损伤的问题而变得复杂。增生（再狭窄）。糖尿病患者更容易发生再狭窄，即使在药物洗脱后支架。随着血管内（例如血管成形术和器械插入）和高度流行的心血管疾病的外科手术（例如，旁路），修复的最佳解决方案运动规则可以称得上具有本质意义动脉损伤后的修复过程是复杂的。损伤后修复的启动良好研究血栓形成后的炎症、细胞增殖和重塑。解决维修过程中知之甚少，特别是，什么构成了“刹车”，以防止过度维修？血小板提供了对抗血管损伤的第一道和关键的防线，最初维持止血。在活化时，血小板还释放生物活性介质如PDGF和血栓烷，促进血小板活化。 VSMC从静止收缩表型向高度合成和增殖细胞的去分化型，促进损伤修复。过度修复，如糖尿病中观察到的内膜增生手术或血管介入后的糖尿病（DM）可能是由于VSMC去分化增强所致，增殖我们将阐述血小板源性miRNAs水平转移到VSMCs的假设，提供了一种新的机制，用于调节VSMC表型转换，防止过度修复，内膜增生我们处于一个独特的位置，以解决我们的假设，血管外科干预和VSMC生物学专业知识（Alan Dardik医学博士和Kathleen Martin博士），血小板专业知识（JohnHwa医学博士，阿威何唐博士），和糖尿病（SilvioInzucchi医学博士， Raimund Herzog医学博士）。在短期内，我们将提出一个新的机制，血小板VSMC 相互作用和动脉损伤修复。从长远来看，这些机械的见解可能会提供新的促进动脉损伤修复的治疗靶点。