Mechanisms of Deep Vein Thrombosis (DVT) and Vein Wall Fibrosis

深静脉血栓（DVT）和静脉壁纤维化的机制

• 批准号: 10651628
• 负责人: Khanh P. Nguyen
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10651628
• 关键词: Academic Training; Acute; Affect; Anatomy; Anti-Inflammatory Agents; Anticoagulants; Anticoagulation; Antithrombin III; Area; Award; Basic Science; Biological Markers; Biology; Biomechanics; Biometry; Blood Vessels; Blood coagulation; Blood flow; Cardiovascular Diseases; Cardiovascular system; Catheters; Chronic; Clinical; Clinical Data; Clinical Research; Clinical Trials; Coagulation Process; Contrast Media; Creativeness; Data Analyses; Data Collection; Deep Vein Thrombosis; Development; Diagnosis; Disease; Double-Blind Method; Extracellular Matrix; Factor Xa; Failure; Family; Fibrosis; Functional disorder; Goals; Growth Factor; Health; Healthcare Systems; Histologic; Hormones; Human; IL8RB gene; Image; Imaging Techniques; Immune; Immune response; Immune system; Immunology; Impairment; Incidence; Incidence Study; Inflammation; Inflammation Process; Inflammatory; Innate Immune System; Interleukin-8; K-Series Research Career Programs; Leadership; Leg; Link; Lower Extremity; Macrophage; Magnetic Resonance; Magnetic Resonance Imaging; Measures; Mediating; Medical; Mentors; Mentorship; Microscopy; Modeling; Modernization; Molecular; Molecular Biology; Morbidity - disease rate; Mus; Natural Immunity; Oral; Oregon; Pathway interactions; Patient Care; Patients; Peptide Receptor; Persons; Physicians; Plasma; Postphlebitic Syndrome; Process; Quality of life; Randomized; Randomized, Controlled Trials; Recurrence; Reflux; Regulation; Relaxin; Reporting; Research Design; Residual state; Resolution; Role; Science; Scientist; Serum; Severities; Signal Transduction; Signs and Symptoms; Surgeon; Surveys; T-Lymphocyte; T2 weighted imaging; TLR4 gene; TLR9 gene; Testing; Therapeutic Agents; Thick; Thrombosis; Thrombus; Tissues; Training; Transgenic Mice; Transgenic Model; Translational Research; Universities; Vascular Diseases; Veins; Venous; Visualization; Warfarin; antifibrotic treatment; biomechanical test; career; clinically relevant; collaborative environment; data management; deep vein; design; didactic education; disability; elastography; feasibility testing; ferumoxytol; graduate school; healing; improved; in vivo; in vivo imaging; microCT; molecular imaging; monocyte; mortality; mouse model; multidisciplinary; neovascularization; neutralizing monoclonal antibodies; neutrophil; novel; patient oriented research; postcapillary venule; pre-clinical; prevent; programs; prospective; radiological imaging; recruit; response; secondary outcome; skills; thrombolysis; thrombotic; ultrasound; vascular injury; venule

This CSR&D VA Career Development Award (CDA-2) will develop Dr. Khanh Nguyen as a vascular surgeon-scientist trained in both basic and translational research approaches to study vascular disease and apply discoveries to improve the care of patients. With the support of an excellent mentorship team at the VA Portland Health Care System (VAPORHCS) and Oregon Health & Science University (OHSU) headed by her primary mentor, Dr. Edward Neuwelt, she will study deep vein thrombosis (DVT), where clots form in the deep veins of the body. Despite modern medical treatment, chronic or recurrent DVT and post thrombotic syndrome (PTS), where signs and symptoms of DVT persist or worsen causing lifelong disability. Recent clinical trials have shown that even with the addition of catheter directed thrombolysis to standard anticoagulation therapy, PTS still occurs. Anticoagulation treatment, primarily with warfarin or direct oral anticoagulants (DOAC) such as rivaroxaban or apixaban, are inadequate to prevent PTS, although some early studies suggest that the DOAC rivaroxaban may decrease the incidence of PTS but does not eliminate it. The goal of this proposal is to understand the process of inflammation and fibrosis in DVT resolution. During DVT healing, these processes may be beneficial by directing tissue remodeling and dissolving thrombus but may be detrimental by damaging vein walls, valves and surrounding tissues; thereby leading PTS. Aim 1 of this proposal will examine the role of relaxin (RLX), that has anti- inflammatory and anti-fibrotic effects in other vascular diseases, on the molecular, structural and biomechanical changes of the thrombus and vein wall during DVT resolution using advanced molecular, immunohistochemical, biomechanical and in-vivo imaging techniques including a novel contrast, ferumoxytol enhanced-Magnetic Resonance Imaging (Fe-MRI). We will use in-vivo mouse models of DVT, transgenic mice with deficiency in RLX (RLX -/-) under anticoagulant conditions (warfarin versus rivaroxaban). Aim 2 will study the incidence of PTS defined by the clinical Villalta score in patients after acute proximal lower extremity DVT that have been randomized to either standard warfarin or rivaroxaban and explore RLX as a plasma biomarker and Fe-MRI as a radiographic biomarker in a small, double blinded, randomized, controlled trial. RLX's potential as an effective anti-inflammatory or anti-fibrotic makes it a promising therapeutic agent for preventing PTS. This award will provide the support for Dr. Nguyen to develop expertise in: (1) advanced molecular and imaging techniques including ultrasound (US), Fe-MRI and in-vivo molecular imaging, (2) pre- clinical approaches and models, (3) training in advanced patient-oriented research including research design, implementation and biostatistics, and (4) professional academic training including management and leadership. To achieve these goals, Dr. Nguyen has assembled a diverse and multidisciplinary team of physicians and scientists and designed a training plan to develop essential skills required to achieve her career goals and complete this scientific proposal. With a combination of hands on scientific training and formal didactic education through OHSU's graduate school programs, she will improve her proficiency in the following specific areas: 1) vascular and molecular biology, 2) immunology, 3) advanced microscopy, 4) Fe-MRI and micro-CT, 4) US including elastography, 5) biomechanical analysis, 6) prospective clinical research design and implementation, 7) clinical data collection and management and 8) data analysis and biostatistics. The creative and collaborative environment at OHSU will allow her to complete the aims in this proposal and achieve her long-term goal of becoming a surgeon-scientist with a focus on vascular biology and venous diseases.

这个CSR＆D VA职业发展奖（CDA-2）将发展Khanh Nguyen博士 在基础研究和转化研究方法中培训的血管外科医生科学家 血管疾病并应用发现以改善患者的护理。在一个支持 VA波特兰医疗保健系统（Vaporhcs）和俄勒冈州Health的优秀指导团队 ＆科学大学（OHSU）由她的主要导师爱德华·诺维尔特（Edward Neuwelt）领导，她将学习 深静脉血栓形成（DVT），其中凝块在人体的深静脉中形成。尽管现代医疗 治疗，慢性或复发性DVT和血栓形成综合征（PTS），符号和符号 DVT的症状持续或恶化，导致终生残疾。最近的临床试验表明 即使在标准抗凝治疗中添加了导管定向溶栓，PTS仍然 发生。抗凝治疗，主要用华法林或直接口服抗凝剂（DOAC）这样 由于利伐沙班或阿普沙班，还不足以防止PTS，尽管一些早期研究表明 DOAC Rivaroxaban可能会降低PT的发生率，但不会消除它。 该建议的目的是了解DVT的炎症和纤维化的过程 解决。在DVT愈合过程中，这些过程可能通过指导组织重塑和 溶解血栓，但可能会因损坏静脉壁，瓣膜和周围组织而有害； 从而领先PT。该提案的目标1将检查具有抗抗素（RLX）的作用（RLX） 其他血管疾病的炎症和抗纤维化作用，分子，结构和结构性疾病 DVT分辨率期间血栓和静脉壁的生物力学变化使用高级 分子，免疫组织化学，生物力学和体内成像技术，包括一种新型 对比度，铁氧基增强的磁共振成像（Fe-MRI）。我们将使用体内鼠标 DVT模型，RLX（RLX - / - ）缺乏的转基因小鼠的模型 （华法林与利伐沙班）。 AIM 2将研究临床Villalta定义的PT的发病率 急性下肢急性下肢DVT后的患者得分 标准华法林或利瓦罗沙班（Rivaroxaban 放射学生物标志物在一个小的双盲，随机，对照试验中。 RLX作为一个潜力 有效的抗炎或抗纤维化使其成为预防PTS的有前途的治疗剂。 该奖项将为Nguyen博士提供支持，以发展专业知识：（1）高级分子 以及包括超声（US），Fe-MRI和体内分子成像的成像技术，（2） 临床方法和模型，（3）先进的面向患者研究的培训，包括研究 设计，实施和生物统计学以及（4）专业的学术培训包括 管理和领导。为了实现这些目标，Nguyen博士聚集了多样化， 多学科的医生和科学家团队，并设计了一项培训计划来制定基本 实现她的职业目标并完成这项科学建议所需的技能。结合 通过OHSU的研究生院课程进行科学培训和正式教育教育， 她将提高以下特定领域的熟练程度：1）血管和分子生物学，2） 免疫学，3）高级显微镜，4）Fe-MRI和Micro-CT，4）我们包括弹性，5） 生物力学分析，6）前瞻性临床研究设计和实施，7）临床数据 收集和管理以及8）数据分析和生物统计学。创意与协作 OHSU的环境将使她能够完成此提案中的目标并长期实现 成为一名外科医生科学家的目标，重点是血管生物学和静脉疾病。