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

• 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
• 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

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.

项目总结