Endothelial Function in Human Peripheral Arteries

描述（由申请人提供）：这份指导的K23提案概述了Kashyap博士在外周动脉疾病（PAD）内皮功能领域的4年培训计划。申请人在血管疾病和血栓-内皮相互作用方面有很强的背景。申请人的长期目标是了解内皮功能对动脉粥样硬化的影响，缺血性临床事件，以及血管内介入治疗的持久性。这将通过教学计划、临床研究指导培训和临床试验方法培训来完成。候选人持续观察到血栓导致内皮功能障碍。先前的实验和初步数据表明，腔动脉血栓通过增加精氨酸酶活性来降低一氧化氮（NO）。通过机械手段去除血栓或溶栓恢复血流，但导致持续的内皮功能障碍。在动物模型中，溶栓联合一氧化氮前体l -精氨酸可改善血栓诱导的内皮功能障碍。有待检验的假设是：A)急性动脉血栓形成通过增加精氨酸酶活性加重内皮功能障碍；B)血栓形成后，局部补充l -精氨酸可通过增加局部一氧化氮水平改善内皮功能。本建议的相关具体目标是：1。评估新鲜截肢标本的人动脉内皮功能，并与精氨酸酶活性、一氧化氮和动脉形态相关。2. 在下肢PAD血管造影时，用血管内超声（IVUS）在体内评估内皮功能。3. 在一项前瞻性双盲研究中比较l -精氨酸和安慰剂在需要溶栓的严重肢体缺血患者中的作用。这些研究结果将有助于更好地了解受动脉粥样硬化影响的外周动脉部位的内皮功能。这一发现将导致靶向治疗停止或改善内皮功能障碍。提出的研究将对PAD患者产生影响，并改善重症缺血患者的临床护理。摘要：人类腿部动脉狭窄可导致动脉凝血和截肢。当血栓形成时，动脉内壁的细胞不能正常工作，即使使用了溶凝剂，也会引起再凝血。我们将测试一种新的凝块溶解组合，它可能改善动脉凝块后的细胞功能和结果。

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.