Alpha-Defensins in perioperative thrombosis

围手术期血栓形成中的α-防御素

基本信息

批准号：
8885365
负责人：
Abd Alroof HIGAZI
金额：
$ 40万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-02 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8885365
关键词：
Address Adherence Animals Anticoagulants Attenuated Biological Markers Bone Marrow Bone Marrow Transplantation Carotid Arteries Clinical Coagulation Process Colchicine Complex Cytolysis Cytoplasmic Granules Data Defensins Deposition Disease Dose Embolism Enzymes Equilibrium Femoral vein Fibrin Fibrinogen Fibrinolysis Genetic Hemorrhage Hemostatic function Human In Vitro Individual Infection Infection prevention Inflammation Investigation Link Lung Measures Mediator of activation protein Medical Methods Modeling Mus Natural Immunity Neutrophil Activation Operative Surgical Procedures Oral Outcome Patients Peptides Perioperative Permeability Plasma Platelet Activation Play Populations at Risk Postoperative Period Prevention Prevention Guidelines Process Property Proteins Publishing Rattus Resistance Risk Risk Estimate Risk Factors Risk Reduction Role Scanning Electron Microscopy Structure Thromboembolism Thrombosis Thrombus Transgenic Mice Transplantation Venous Venous Thrombosis Wound Healing alpha-Defensins antimicrobial peptide bariatric surgery base biophysical analysis biophysical techniques crosslink effective intervention in vivo inhibitor/antagonist injured insight knock-down man meetings neutrophil novel novel strategies polymerization prevent prophylactic public health relevance reconstitution research study small hairpin RNA

项目摘要

DESCRIPTION (provided by applicant): Surgery increases the risk of thrombosis but prevention and management of thromboembolic disease in the perioperative period is complicated by the risk of hemorrhage. Neutrophils (PMNs) play a vital role in wound healing, but their contribution to perioperative thrombosis and implications for thromboprophylaxis are now emerging. Adherence of PMNs to wounds and to the vasculature generates a unique localized sequestrum enriched in enzymes and antimicrobial peptides protected from plasma inhibitors that contribute to innate immunity in part through the orderly formation and dissolution of fibrin. We posit that post-operative and persistent inflammation disrupt this balance, predisposing to thrombosis by promoting formation and persistence of fibrin. We have previously observed that a-defensins (a-def), antimicrobial peptides that constitute 5% of total human PMN protein that are released upon activation, promote clotting and inhibit fibrinolysis. The absence of a-def in murine PMNs has hindered a better understanding of how these peptides contribute to thromboembolic disease in the perioperative setting. Using a novel transgenic mouse that expresses PMN a-def (Def++), we show that a-def circulates in a complex with fibrinogen and promotes polymerization and retraction of fibrin in vitro, deposits in the vasculature, induces occlusive arterial and venous thrombosis, and inhibits lysis of pulmonary emboli in vivo. These pathogenic properties can be transferred to wild type animals by transplanting bone marrow from Def++ mice and can be prevented and reversed by immunodepleting PMNs or by inhibiting a-def release using colchicine. We now propose an integrated approach to understanding the mechanism and implications of PMN a-def on perioperative thrombosis by examining: a) The biophysical effects of a-def on clot formation and structure; b) The mechanism of accelerated thrombosis and impaired fibrinolysis in Def++ mice and the salutary effect of blocking a-def release; and c) The utility of a-def expression as a biomarker for risk of venous thromboembolism post- surgery. These studies will provide insight into an unappreciated contribution of PMN a-def to arterial and venous thrombosis, identify novel genetic and protein biomarkers of patients at risk for surgery related thrombosis and provide evidence for the use of a safe and effective intervention to prevent thrombosis in the perioperative period.

描述（由适用提供）：手术增加了血栓形成的风险，但在周期期间预防和治疗血小板疾病的风险因出血风险而复杂。中性粒细胞（PMN）在伤口愈合中起着至关重要的作用，但是它们对周期性血栓形成的贡献及其对血栓预防的影响现已出现。 PMN遵守胜利和脉管系统会产生一种独特的局部锁骨，富集于酶和抗菌胡椒中，可保护的抗菌辣椒免受血浆抑制剂的保护，这些抑制剂可通过有序的形成和溶解，从而有助于先天免疫我们先前已经观察到A-二防御素（A-脱Fef），抗菌胡椒质，占人类总PMN蛋白的5％，这些蛋白在激活，促进服装和抑制纤维蛋白溶解后释放。在鼠PMN中缺乏A-DEF，阻碍了对这些胡椒粉如何使用一种表达PMN A-DEF（DEF ++）的新型转基因小鼠的贡献的更好的了解，我们表明，A-DEF与纤维蛋白原相循环，并促进纤维蛋白的聚合和恢复纤维蛋白的纤维蛋白，并在纤维蛋白中恢复，并涉及偶然的动物，并在偶然的范围内散发出多种作用。体内肺栓塞。这些致病性能可以通过从DEF ++小鼠中移植骨髓来转移到野生型动物中，并且可以通过免疫驱动PMN或使用秋水仙碱抑制A-DEF释放来预防和逆转。现在，我们提出了一种综合方法，通过检查：a）A-DEF对凝块形成和结构的生物物理影响； b）在DEF ++小鼠中加速血栓形成和纤维蛋白溶解的机制以及阻断A-DEF释放的有益作用； c）A-DEF表达作为外科手术后静脉血栓形成风险的生物标志物。这些研究将提供对PMN A-DEF对动脉和静脉血栓形成的不适当贡献的洞察力，确定具有与手术相关的血栓形成风险的患者的新型遗传和蛋白质生物标志物，并为使用安全有效的干预措施提供了预防周期性血栓形成的证据。