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

这项CSR&D VA职业发展奖(CDA-2)将把Khanh Nguyen博士培养成一名 血管外科医生-受过基本研究方法和翻译研究方法培训的科学家 血管疾病和应用的发现，以改善对患者的护理。在联合国的支持下 退伍军人管理局波特兰医疗保健系统(VAPORHCS)和俄勒冈健康中心优秀的导师团队 在她的主要导师爱德华·纽韦尔特博士的领导下，她将研究 深静脉血栓形成(DVT)，在身体的深静脉中形成凝块。尽管现代医学 治疗，慢性或复发的深静脉血栓形成和血栓形成后综合征(PTS)，其中体征和 深静脉血栓的症状持续存在或恶化，导致终生残疾。最近的临床试验表明， 即使在标准抗凝治疗的基础上增加导管定向溶栓治疗，PTS仍然 发生。抗凝治疗，主要使用华法林或直接口服抗凝剂(DOAC)，如 如利伐沙班或阿皮沙班，不足以预防PTS，尽管一些早期研究表明 DOAC利伐沙班可以降低PTS的发生率，但不能消除它。 这项建议的目标是了解深静脉血栓的炎症和纤维化过程。 决议。在深静脉血栓愈合过程中，这些过程可能通过引导组织重塑和 溶解血栓，但可能损害静脉壁、瓣膜和周围组织； 从而引领了PTS。这项提案的目标1将检查松弛素(RLX)的作用，它具有抗 在其他血管疾病中的炎症和抗纤维化作用，对分子、结构和 ADVT溶栓治疗过程中血栓和静脉壁的生物力学变化 分子、免疫组织化学、生物力学和体内成像技术，包括一种新的 对比剂阿魏酸甘油酯增强磁共振成像(Fe-MRI)。我们将使用体内的小鼠 抗凝状态下RLX基因缺陷(RLX-/-)转基因小鼠DVT模型的建立 (华法林与利伐沙班)。目的2将研究PTS的发病率定义为临床绒毛 随机分为以下两组的急性近端深静脉血栓形成患者的评分 标准华法林或利伐沙班，探索RLX作为血浆生物标志物和Fe-MRI作为 一项小型、双盲、随机、对照试验中的放射生物标记物。RLX作为一种 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。 该奖项将支持阮博士在以下方面发展专业知识：(1)先进分子 和成像技术，包括超声(US)、Fe-MRI和体内分子成像，(2)Pre- 临床方法和模式，(3)以病人为中心的高级研究培训，包括研究 设计、实施和生物统计；以及(4)专业学术培训，包括 管理和领导力。为了实现这些目标，阮氏博士组建了一个多样化的 由医生和科学家组成的多学科团队，并设计了培训计划以开发必要的 实现她的职业目标和完成这项科学提案所需的技能。通过组合使用 通过OHSU的研究生院项目进行科学培训和正规的教学教育， 她将提高自己在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)US，包括弹性成像，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 收集和管理以及数据分析和生物统计。创造性和协作性 OHSU的环境将使她能够完成这项提案中的目标，并实现她的长期目标 目标是成为一名外科医生-科学家，专注于血管生物学和静脉疾病。

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.