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: 10700953
• 负责人: Rick Mathews
• 金额: $ 5.27万
• 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/10700953
• 关键词: Academic Medical Centers; Adhesions; Affect; Age; Animals; Antibodies; Anticoagulation; 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; Hematology; Hemostatic function; Heparin Cofactor II; Heparitin Sulfate; Hyaluronan; Impairment; In Vitro; Incidence; Inferior vena cava structure; Infiltration; Inflammation; Inflammatory; Inflammatory Infiltrate; Interleukin-1 beta; Interleukin-13; Intervention Studies; Investigation; Laboratories; Leadership; Macrophage; Magnetic Resonance Imaging; Measures; Mediator; Membrane; Mentorship; Modeling; Mus; Operative Surgical Procedures; Oregon; PECAM1 gene; Pathway interactions; Patients; Perfusion; Permeability; Persons; Phenotype; Physicians; Platelet Activation; Platelet-Derived Growth Factor; Play; Postoperative Period; Postphlebitic Syndrome; Prednisone; Process; Productivity; Proliferating; Proteoglycan; Quality of life; Recurrence; Research Proposals; Resolution; Role; Saline; Science; Scientist; Senior Scientist; Signs and Symptoms; Smooth Muscle Myocytes; Stains; Surface; TNF gene; Techniques; Thrombin; Thrombophilia; Thrombosis; Thrombus; Training; Transforming Growth Factor beta; Universities; Vasodilation; Veins; Venous; Weight; career; career development; cell injury; constriction; deep vein; design; disability; ferumoxytol; glycosylation; in vivo; injured; monocyte; monolayer; mouse model; neutrophil; optimal treatments; sham surgery; 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.

项目概要 静脉血栓栓塞性疾病是心血管死亡的第三大常见原因 疾病。尽管在标准抗凝治疗中添加了导管定向溶栓，但复发性 深静脉血栓形成 (DVT) 和随后的血栓后综合症 (PTS)，其中体征和症状 DVT 持续存在或随着血栓消退而恶化，仍会导致长期残疾。从而更好地理解 需要了解 DVT 形成和消退的基本机制。 为了形成 DVT，必须发生内皮细胞 (EC) 损伤。最近，EC 糖萼 (eGCX) 糖蛋白、蛋白聚糖和相关糖胺聚糖 (GAG) 的膜结合网已经出现 作为一个多功能表面层，能够调节血管舒张、炎症、增殖和 凝血途径。 3 个最著名的 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 和非凝血酶的结合位点相关。 循环因子 XI (FXI)。这些关键凝血成分的 GAG 结合表明存在不明确的 目前 GAG 在血栓形成和消退中的作用尚不清楚，有必要进一步研究 机制调查。 该提案的目标是阐明 eGCX 调节 DVT 形成的机制作用以及 解决。我的假设认为，受伤的 eGCX 会通过增加血小板 EC 来促进 DVT 形成 通过释放非循环 FXI 相互作用并激活内在凝血途径。此外， 受损的 eGCX 将通过增加炎症 (M1) 单核细胞浸润到血栓中来损害 DVT 的缓解 和静脉壁。在目标 1 中，我将确定 eGCX GAG 在血小板活化和血栓形成中的作用 在野生型 CD1 小鼠中使用腔静脉收缩 DVT 模型。在目标 2 中，我将确定 eGCX GAG 的作用 引起血栓后静脉壁变化。这项研究将有可能确定相关的治疗靶点 直接影响 DVT 的形成和消退，为介入研究铺平道路，支持 开发选择性、安全且有效的抗血栓药物的基本原理。这些研究将 在俄勒冈州的主要学术医疗中心俄勒冈健康与科学大学进行 生物医学工程和血管外科系在 Monica Hinds 博士的共同指导下， 博士和 Khanh Nguyen 博士（医学博士）。 PI 得到由资深科学家和医生组成的导师团队的支持 具有血管病理生理学、血栓形成和血管外科方面的专业知识。职业发展活动 包括小鼠手术、体外和体内分析技术以及凝血和血管方面的培训 病理生理学，以及沟通和领导技能培训。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一个富有成效和 转化血管病理生理学实验室与血管外科实践紧密结合。