The Impact of Thrombosis and Antithrombotic Therapy on Peripheral Artery Disease

血栓形成和抗血栓治疗对周围动脉疾病的影响

• 批准号: 10558731
• 负责人: Aaron W. Aday
• 金额: $ 18.54万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10558731
• 关键词: Academic Medical Centers; Acute; Adhesions; Amputation; Antithrombin III; Arterial Fatty Streak; Arteries; Aspirin; Atherosclerosis; Biological; Blood Coagulation Factor; Blood Platelets; Blood Vessels; Cardiovascular system; Cell surface; Cessation of life; Chronic; Clinical; Clinical Research; Clinical Trials; Coagulation Process; Coronary Arteriosclerosis; Data; Development; Dose; Double-Blind Method; Endothelium; Environment; Epidemiologic Methods; Epidemiology; Event; Factor V; Factor Xa; Fibrinolytic Agents; Future; Genetic; Goals; Hemorrhage; High Prevalence; Human; In Vitro; Individual; Inflammation; Intervention; Intervention Studies; Investigation; K-Series Research Career Programs; Knowledge; Lead; Leg; Life; Limb structure; Link; Lower Extremity; Mediating; Mediator; Medicine; Mendelian randomization; Mentored Patient-Oriented Research Career Development Award; Mentorship; Methods; Morbidity - disease rate; Myocardial Infarction; Outcome; PAR-1 Receptor; Pathway interactions; Patients; Peripheral arterial disease; Persons; Pharmaceutical Preparations; Physiological; Placebo Control; Platelet Activation; Play; Positioning Attribute; Randomized; Research; Research Personnel; Risk; Risk Reduction; Role; Signal Transduction; Stenosis; Stroke; Testing; Therapeutic Studies; Thrombin; Thrombophilia; Thrombosis; Thrombus; Translational Research; Variant; Vascular Endothelium; Vitamin K; Warfarin; antagonist; cardiovascular risk factor; career; clinical trial implementation; design; experience; genetic epidemiology; genome-wide analysis; high risk; improved; inhibitor; instructor; limb ischemia; mortality; new therapeutic target; novel; patient oriented; patient population; personalized medicine; platelet function; pleiotropism; pre-clinical; randomized trial; skills; stroke risk; thrombolysis; thrombotic; tool; translational research program

The applicant, Aaron W. Aday, MD, is an Instructor of Medicine in the Division of Cardiovascular Medicine at Vanderbilt University Medical Center. The applicant's goal is to become an independent cardiovascular investigator studying the thrombotic mechanisms underlying peripheral artery disease (PAD) development. This application for a K23 Mentored Patient-Oriented Research Career Development Award describes a focused plan for the applicant to acquire the research skills and expertise required to transition into an independent investigator under the primary mentorship of Joshua A. Beckman, MD. The proposal centers on the study of thrombosis and antithrombotic therapy in PAD. PAD is a highly prevalent atherosclerotic disease associated with significant cardiovascular morbidity and mortality. However, there remain notable gaps in our knowledge of the biologic pathways involved in PAD development. Recent data suggest important contributions of thrombosis, through both coagulation cascade activation and platelet activation, to the development of PAD. However, the mechanisms of thrombosis and platelet activation contributing to PAD in humans are not fully known. The specific aims of the proposed research are: (Aim 1) to quantify the risk conferred by activation of thrombotic pathways, in addition to traditional cardiovascular risk factors, on PAD using Mendelian randomization; (Aim 2a) to test the hypothesis that low-dose rivaroxaban, a clotting factor Xa inhibitor, improves macro- and microvascular endothelial function in humans with PAD; and (Aim 2b) to test the hypothesis that low-dose rivaroxaban reduces PAR-1- mediated platelet activation while also facilitating thrombolysis and reducing inflammation via downstream signaling. The candidate has a strong background in both clinical vascular genetics as well as epidemiology of PAD. The proposed project will afford him new expertise in several key domains, including (1) genetic epidemiology and Mendelian randomization methods, (2) design and implementation of clinical trials, (3) patient-oriented vascular physiologic studies, and (4) translational investigations of thrombosis and platelet function. Vanderbilt University Medical Center has an ideal environment to support the candidate's investigational career. He will be supported by an outstanding mentorship team with extensive experience in clinical and translational cardiovascular research. However, the proposal will also provide Dr. Aday the opportunity to develop into a leading investigator with unique expertise in genetic epidemiology as well as mechanistic clinical trials focusing on PAD. Data from the proposed studies will also serve as the basis for future mechanistic and interventional studies (i.e. R01) of thrombosis in PAD. The support of this Career Development Award will provide Dr. Aday with the tools necessary to lead his own independent clinical and translational research program.

申请人Aaron W. Aday，医学博士是心血管医学司的医学讲师 范德比尔特大学医学中心。申请人的目标是成为独立的心血管 研究人员研究了外周动脉疾病（PAD）发育的血栓性机制。 这项针对K23指导的以患者为导向的研究职业发展奖的申请描述了 申请人的重点计划，以获取过渡到过渡到的研究技能和专业知识 约书亚·A·贝克曼（Joshua A. Beckman）医学博士的主要指导下的独立调查员。提案以 PAD中血栓形成和抗血栓疗法的研究。 PAD是一种高度普遍的动脉粥样硬化疾病，与明显的心血管发病率和 死亡。但是，我们对PAD中涉及的生物学途径的了解仍然存在显着差距 发展。最近的数据表明，通过两种凝血级联 激活和血小板激活，以开发PAD。但是，血栓形成和 导致人体垫的血小板激活尚不清楚。提议的具体目的 研究是：（目标1）除了 传统的心血管危险因素，使用孟德尔随机化垫； （AIM 2A）检验假设 那种低剂量的利伐沙班是一种凝血因子Xa抑制剂，可改善宏观和微血管内皮 用垫子在人类中的功能； （AIM 2B）测试低剂量利瓦沙班的假设减少了PAR-1- 介导的血小板激活，同时还促进溶栓并通过下游减少炎症 信号。 候选人在临床血管遗传学以及PAD的流行病学方面都有很强的背景。这 拟议的项目将为他提供多个关键领域的新专业知识，包括（1）遗传流行病学和 孟德尔随机化方法，（2）临床试验的设计和实施，（3）面向患者的血管 生理研究，以及（4）血栓形成和血小板功能的翻译研究。范德比尔特 大学医学中心有一个理想的环境来支持候选人的调查生涯。他会的 得到一支杰出的指导团队的支持，在临床和翻译方面拥有丰富的经验 心血管研究。但是，该提案还将为Aday博士提供机会发展成一个 领先的研究者在遗传流行病学和机械临床试验方面具有独特的专业知识。 在垫子上。拟议研究的数据还将作为未来机械和介入的基础 PAD中血栓形成的研究（即R01）。该职业发展奖的支持将为Aday博士提供 借助领导自己独立的临床和转化研究计划所需的工具。