Endothelial Function in Human Peripheral Arteries

人类外周动脉的内皮功能

• 批准号: 7640545
• 负责人: VIKRAM S KASHYAP
• 金额: $ 13.67万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7640545
• 关键词: 3-nitrotyrosine; Acute; Affect; Aftercare; Amino Acids; Amputation; Angiography; Angioplasty; Animal Model; Area; Arginine; Arterial Fatty Streak; Arteries; Atherosclerosis; Biological Assay; Blood flow; Bypass; C-reactive protein; Catheters; Cell Line; Cell physiology; Chronic; Clinical; Clinical Research; Clinical Trials; Coagulation Process; Coronary Vessels; Coupled; Data; Dose; Double-Blind Method; Event; Excision; Foundations; Functional disorder; Glucose; Glycosylated hemoglobin A; Grant; Histology; Homocysteine; Homocystine; Human; Inflammation; Intervention; Ischemia; Lead; Leg; Legal patent; Limb structure; Low-Density Lipoproteins; Lower Extremity; Mass Spectrum Analysis; Measures; Mechanics; Mediating; Mentors; Methodology; Methods; Modeling; Morphology; Necrosis; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitrites; Organ; Outcome; Patients; Peripheral; Peripheral arterial disease; Placebos; Plasma; Procedures; Process; Proteins; Reperfusion Therapy; Research Personnel; Research Training; Risk Factors; Sampling; Serum; Serum Markers; Site; Specimen; Supplementation; Testing; Thrombin; Thrombolytic Therapy; Thrombosis; Thrombus; Time; Training; Training Programs; Ultrasonography; Vascular Diseases; Vasodilation; Work; arginase; atherogenesis; base; clinical care; improved; in vivo; insight; novel; oxidation; programs; prospective; research study; response; thrombolysis; virtual

DESCRIPTION (provided by applicant): This mentored K23 proposal outlines the 4 year training program for Dr. Kashyap in the area of endothelial function in peripheral arterial disease (PAD). The applicant has a strong background in vascular disease and thrombus-endothelial interaction. The long-term objective of the applicant is to understand the effect of endothelial function on atherogenesis, ischemic clinical events, and durability of endovascular intervention in PAD. This will be accomplished with a program of didactics, mentored training in clinical research, and training in clinical trial methodology. The candidate has made the persistent observation that thrombus causes endothelial dysfunction. Previous experiments and preliminary data indicate that luminal arterial thrombus decreases nitric oxide (NO) by increasing arginase activity. Removal of the thrombus by mechanical means or dissolution with thrombolysis restores blood flow but leads to persistent endothelial dysfunction. In animal models, thrombolysis coupled with NO's precursor, L-arginine, ameliorates thrombus induced endothelial dysfunction. The hypotheses to be tested are A) Acute arterial thrombosis worsens endothelial dysfunction by increasing arginase activity and B) Endothelial function after thrombosis can be improved with regional L-arginine supplementation by increasing local nitric oxide levels. The interrelated specific aims for this proposal are: 1. Assess endothelial function in human arteries from fresh amputation specimens and correlate with arginase activity, NO, and arterial morphology. 2. Assess endothelial function with Intravascular Ultrasound (IVUS) in vivo at the time of angiography for lower extremity PAD. 3. Compare L-arginine to placebo in a prospective, double-blind study in patients with critical limb ischemia requiring thrombolysis. The results of these studies will lead to a better understanding of endothelial function directly at the sites of peripheral arteries affected by atherosclerosis. This insight will lead to targeted therapies to halt or improve endothelial dysfunction. The proposed studies will impact patients with PAD and improve clinical care of patients with critical ischemia. Lay Summary: Narrowing in the leg arteries of humans can lead to clotting of the arteries and amputation. When clots form, the cells lining of the arteries do not work correctly and can cause re-clotting despite using clot-dissolving agents. We will test a novel clot-dissolving combination that may improve cellular function and outcomes after artery clotting.

描述（由申请人提供）：该指导的K23提案概述了Kashyap博士在外周动脉疾病（PAD）领域的Kashyap博士的4年培训计划。申请人在血管疾病和血栓 - 内皮相互作用方面具有强大的背景。申请人的长期目的是了解内皮功能对动脉粥样硬化，缺血性临床事件以及血管内干预的耐用性的影响。这将通过教学品，指导临床研究的培训以及临床试验方法的培训来完成。候选人已经持续观察到血栓引起内皮功能障碍。先前的实验和初步数据表明，腔动脉血栓通过增加精氨酸活性来降低一氧化氮（NO）。通过机械手段去除血栓或用溶栓溶解可恢复血液的流动，但导致持续的内皮功能障碍。在动物模型中，溶栓结合了NO的前体L-精氨酸，可以改善血栓引起的内皮功能障碍。要测试的假设是a）急性动脉血栓形成通过增加精氨酸酶活性和b）血栓形成后的内皮功能加剧了内皮功能障碍，可以通过增加局部一氮氧化物水平来改善血栓形成后的内皮功能。该建议的相互关联的特定目的是：1。通过新鲜截肢标本评估人动脉中的内皮功能，并与精氨酸酶活性，NO和动脉形态相关。 2。在血管造影时，通过体内用血管内超声（IVU）评估内皮功能。 3。将L-精氨酸与安慰剂进行比较，对需要溶栓的临界肢体缺血患者的前瞻性双盲研究。这些研究的结果将导致直接在受动脉粥样硬化影响的外周动脉部位直接了解内皮功能。这种见解将导致靶向疗法停止或改善内皮功能障碍。拟议的研究将影响PAD患者，并改善临界缺血患者的临床护理。摘要摘要：在人类的腿部动脉中狭窄会导致动脉凝结和截肢。当形成凝块时，动脉的细胞内壁无法正常工作，尽管使用了凝块溶解剂，但仍可能导致重新关闭。我们将测试一种新型的凝块溶解组合，可以改善动脉凝结后的细胞功能和结果。