Role of glycosaminoglycans (GAGs) in deep vein thrombus formation and resolution

糖胺聚糖（GAG）在深静脉血栓形成和消退中的作用

基本信息

批准号：
10463067
负责人：
Rick Mathews
金额：
$ 5.18万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-27 至 2026-07-26
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10463067
关键词：
Academic Medical Centers Adhesions Affect Age Animals Antibodies Anticoagulation Antithrombins Binding Binding Sites Biomedical Engineering Blood Blood Platelets Blood Vessels Blood flow CCL2 gene CD14 gene Cardiovascular Diseases Catheters Cause of Death Cell Communication Cell Proliferation Chondroitin Sulfates Coagulation Process Communication Complete Blood Count Data Deep Vein Thrombosis Development Disease Doctor of Philosophy Endothelial Cells Enzymes Etiology Exhibits Factor XI Factor XIa Fibrin Fibrinolytic Agents Flow Cytometry Functional disorder Genes Glycocalyx Glycoproteins Glycosaminoglycan Degradation Pathway Glycosaminoglycans Goals Health Sciences Hematology Hemostatic function Heparin Cofactor II Heparitin Sulfate Hyaluronan Impairment In Vitro Incidence Inferior vena cava structure Infiltration Inflammation Inflammatory Interleukin-1 beta Interleukin-13 Intervention Studies Investigation Laboratories Leadership Magnetic Resonance Imaging Measures Mediator of activation protein Membrane Mentorship Modeling Mus Operative Surgical Procedures Oregon PECAM1 gene Pathway interactions Patients Permeability Persons Phenotype Physicians Platelet Activation Platelet-Derived Growth Factor Play Postoperative Period Postphlebitic Syndrome Prednisone Process Proteoglycan Quality of life Recurrence Research Proposals Resolution Role Saline Scientist Senior Scientist Signs and Symptoms Smooth Muscle Myocytes Stains Surface TNF gene Techniques Thrombophilia Thrombosis Thrombus Training Transforming Growth Factor beta Universities Vasodilation Veins Venous Weight career career development cell injury constriction deep vein design disability ferumoxytol in vivo injured macrophage monocyte monolayer mouse model neutrophil optimal treatments skills therapeutic target thrombolysis thrombotic ultrasound venous thromboembolism

Academic Medical Centers Adhesions Affect Age Animals Antibodies Anticoagulation Antithrombins Binding Binding Sites Biomedical Engineering Blood Blood Platelets Blood Vessels Blood flow CCL2 gene CD14 gene Cardiovascular Diseases Catheters Cause of Death Cell Communication Cell Proliferation Chondroitin Sulfates Coagulation Process Communication Complete Blood Count Data Deep Vein Thrombosis Development Disease Doctor of Philosophy Endothelial Cells Enzymes Etiology Exhibits Factor XI Factor XIa Fibrin Fibrinolytic Agents Flow Cytometry Functional disorder Genes Glycocalyx Glycoproteins Glycosaminoglycan Degradation Pathway Glycosaminoglycans Goals Health Sciences Hematology Hemostatic function Heparin Cofactor II Heparitin Sulfate Hyaluronan Impairment In Vitro Incidence Inferior vena cava structure Infiltration Inflammation Inflammatory Interleukin-1 beta Interleukin-13 Intervention Studies Investigation Laboratories Leadership Magnetic Resonance Imaging Measures Mediator of activation protein Membrane Mentorship Modeling Mus Operative Surgical Procedures Oregon PECAM1 gene Pathway interactions Patients Permeability Persons Phenotype Physicians Platelet Activation Platelet-Derived Growth Factor Play Postoperative Period Postphlebitic Syndrome Prednisone Process Proteoglycan Quality of life Recurrence Research Proposals Resolution Role Saline Scientist Senior Scientist Signs and Symptoms Smooth Muscle Myocytes Stains Surface TNF gene Techniques Thrombophilia Thrombosis Thrombus Training Transforming Growth Factor beta Universities Vasodilation Veins Venous Weight career career development cell injury constriction deep vein design disability ferumoxytol in vivo injured macrophage monocyte monolayer mouse model neutrophil optimal treatments skills therapeutic target thrombolysis thrombotic ultrasound venous thromboembolism

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项目摘要

PROJECT SUMMARY Venous thromboembolism disorders represent the third most common cause of death from cardiovascular disease. Despite the addition of catheter directed thrombolysis to standard anticoagulation therapy, recurrent deep vein thrombosis (DVT) and subsequent post-thrombotic-syndrome (PTS), where the signs and symptoms of DVT persist or worsen with thrombus resolution, still cause long term disability. Thus, a better understanding of the basic mechanisms of DVT formation and resolution is needed. In order for a DVT to form, endothelial cell (EC) injury must occur. Recently, the EC glycocalyx (eGCX), a membrane bound mesh of glycoproteins, proteoglycans, and associated glycosaminoglycans (GAGs), has come into focus as a multifunctional surface layer capable of regulating vasodilation, inflammation, proliferation, and coagulation pathways. The 3 most prominent eGCX GAGs, heparan sulfate (HS), chondroitin sulfate (CS), and hyaluronan (HA), have been associated with binding sites for anti-thrombin, heparin cofactor II, and non- circulating factor XI (FXI). GAG binding of these critical coagulation components suggests an ambiguous and currently unclarified role for GAGs in thrombus formation and resolution, warranting further mechanistic investigation. The goal of this proposal is to elucidate the mechanistic role by which the eGCX regulates DVT formation and resolution. My hypothesis maintains that an injured eGCX will bolster DVT formation by increasing platelet-EC interactions and activating the intrinsic clotting pathway, via release of non-circulating FXI. Furthermore, the injured eGCX will impair DVT resolution by increasing inflammatory (M1) monocyte infiltration into the thrombus and the vein wall. In Aim 1, I will determine the role of eGCX GAGs in platelet activation and thrombus formation using a caval constriction DVT model in wildtype CD1 mice. In Aim 2, I will determine the role of eGCX GAGs in causing post-thrombotic vein wall changes. This study will potentially identify relevant therapeutic targets that directly affect DVT formation and resolution, paving the way for interventional studies and supporting the rationale for the development of selective, safe, and effective antithrombotic agents. These studies will be performed at Oregon's primary academic medical center, the Oregon Health and Science University in the Departments of Biomedical Engineering and Vascular Surgery under the co-mentorship of Dr. Monica Hinds, PhD and Dr. Khanh Nguyen, MD. The PI is supported by a mentorship team of senior scientists and physicians with expertise in vascular pathophysiology, thrombosis, and vascular surgery. Career development activities include training in mouse surgery, in vitro and in vivo analysis techniques, and coagulation and vascular pathophysiology, as well as training in communication and leadership skills. This training is designed to support the PI's career goals of becoming a physician-scientist with a long-term career goal of leading a productive and translational vascular pathophysiology laboratory with a tightly integrated vascular surgery practice.

项目摘要静脉血栓栓塞障碍是心血管造成的第三大死亡原因疾病。尽管在标准抗凝治疗中添加了导管定向溶栓，但经常性深静脉血栓形成（DVT）和随后的脑栓塞后综合征（PTS），其中体征和症状 DVT的持续或通过血栓分辨率持续或恶化，仍然会导致长期残疾。因此，更好的理解需要DVT形成和分辨率的基本机制。为了形成DVT，必须发生内皮细胞（EC）损伤。最近，ec糖脂（EGCX），a 糖蛋白，蛋白聚糖和相关的糖胺聚糖（gags）的膜结合网已经来了作为一个多功能表面层，能够调节血管舒张，炎症，增殖和凝结途径。 3个最突出的EGCX GAG，硫酸乙酰肝素（HS），硫酸软骨素（CS）和透明质酸（HA）与抗凝血酶，肝素辅因子II和非 - 循环因子XI（FXI）。这些临界凝血成分的插科打结合表明是模棱两可的目前在血栓形成和解决方案中，插科打的角色未汇总作用，需要进一步保证机械调查。该建议的目的是阐明EGCX调节DVT形成和的机理作用解决。我的假设坚持认为，受伤的EGCX将通过增加血小板-EC来增强DVT形成通过释放非循环FXI的释放，相互作用并激活固有的凝血途径。此外，受伤的EGCX将通过增加炎症（M1）单核细胞浸润到血栓中损害DVT的分辨率和静脉墙。在AIM 1中，我将确定EGCX GAG在血小板激活和血栓形成中的作用使用WildType CD1小鼠中的Caval收缩DVT模型。在AIM 2中，我将确定EGCX插科打的作用在引起脉动后静脉壁变化时。这项研究将有可能确定相关的治疗靶标直接影响DVT的形成和分辨率，为介入研究铺平了道路并支持开发选择性，安全和有效的抗血栓形成剂的基本原理。这些研究将是在俄勒冈州初级学术医学中心，俄勒冈州健康与科学大学莫妮卡·辛德斯（Monica Hinds）博士的同学生物医学工程和血管外科部门博士学位和医学博士Khanh Nguyen博士。 PI得到了高级科学家和医生的指导团队的支持具有血管病理生理学，血栓形成和血管手术方面的专业知识。职业发展活动包括小鼠手术，体外和体内分析技术的培训，以及凝血和血管病理生理学以及沟通和领导能力的培训。该培训旨在支持 PI的职业目标是成为一名医师科学家，其长期职业目标是领导生产力和具有紧密整合的血管手术实践的翻译血管病理生理实验室。