Endothelial Function in Human Peripheral Arteries

描述(由申请者提供)：这份K23指导性建议书概述了Kashyap博士在外周动脉疾病(PAD)内皮功能领域的4年培训计划。应聘者在血管疾病和血栓-血管内皮细胞相互作用方面有很强的背景。申请者的长期目标是了解血管内皮细胞功能对动脉粥样硬化形成、缺血性临床事件以及PAD血管内介入治疗的持久性的影响。这将通过一个教学计划、临床研究指导培训和临床试验方法论培训来完成。这位候选人坚持认为血栓会导致内皮功能障碍。先前的实验和初步数据表明，管腔动脉血栓通过增加精氨酸酶活性来降低一氧化氮(NO)。通过机械方法清除血栓或溶栓后溶解血栓可以恢复血流，但会导致持续性的内皮功能障碍。在动物模型中，溶栓联合NO前体L精氨酸可改善血栓所致的内皮功能障碍。需要检验的假设是：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)局部补充L精氨酸可通过提高局部一氧化氮水平改善血栓形成后的内皮功能。这项建议相关的具体目标是：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.血管内超声(IVUS)评价血管内皮细胞功能。3.在一项对需要溶栓治疗的严重肢体缺血患者进行的前瞻性双盲研究中，比较了L-精氨酸和安慰剂。这些研究的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。这一见解将导致有针对性的治疗，以阻止或改善内皮功能障碍。拟议的研究将影响PAD患者，并改善对严重缺血患者的临床护理。莱斯摘要：人类腿部动脉狭窄会导致动脉凝结和截肢。当血栓形成时，动脉衬里的细胞不能正常工作，即使使用了溶解血栓的试剂，也可能导致重新凝血。我们将测试一种新的溶解血栓的组合，该组合可能会改善细胞功能和动脉凝血后的结果。

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.