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.

CSR&D VA职业发展奖（CDA-2）将培养Khanh Nguyen博士