ENDOTHELIAL DYSFUNCTION IN CORONARY ATHEROSCLEROSIS

作为一名对心肌梗死的基本机制感兴趣的心脏病学家， 缺血，我的主要职业目标是了解 内皮功能紊乱在动脉粥样硬化中的作用及其机制 导致血管张力异常和血栓形成。 我 细胞生物学和临床研究的双重训练使我在一个 在这方面的优势，因为很少有心脏病专家 开发了必要的技能，以应用来自 血管生物学对心血管疾病患者的影响。 这 申请是在我职业生涯的一个关键点，因为我完成了我的 向完全独立的研究状态过渡。 对于这个新兴的 缩小基础研究和临床研究之间的差距， 继续发展将需要良好的结构和保护的时间。 的 制度环境将有利于这一职业战略 如果我的工资支持来自研究来源，我将继续发展。 这里介绍的研究集中在定义如何存在 患者冠状动脉粥样硬化的影响 内皮依赖性血管舒张剂和血管收缩剂反应。 一 研究计划提出，利用新的见解，从 实验室有三个具体目标。 第一个将 测试人类内皮血管舒张功能障碍的假设 冠状动脉导致缩窄肌对 儿茶酚胺 第二个具体目标将检验以下假设： 内皮衍生的收缩因子（多肽内皮素，如 以及前列腺素类因子）是由人动脉粥样硬化 动脉在不适当的大量响应刺激已知， 导致血管收缩增强，从而有助于发展 心肌缺血 第三个具体目标是检查患者 从实验研究中得出的概念， 胆固醇能改善内皮依赖性血管功能， 血管腔大小的重要变化。 这些研究应 扩大我们的知识的机制和治疗异常 收缩人冠状动脉，并促进临床尝试 来控制活动性缺血

As a cardiologist interested in the basic mechanisms of myocardial ischemia, my primary career objective is to gain an understanding of the role of disturbed endothelial function in atherosclerosis and how it contributes to abnormalities of vasomotor tone and to thrombosis. My dual training in cell biology and clinical research places me in an advantageous position in this regard, since few cardiologists have developed the necessary skills to apply new insights derived from vascular biology to patients with cardiovascular diseases. This application comes at a crucial point in my career as I complete my transition toward fully independent research status. For this burgeoning interest in closing the gap between basic and clinical research to continue to evolve will require well structured and protected time. The institutional environment will be conducive to this strategy for career development provided that my salary support comes from research sources. The studies presented here focus on defining how the presence of atherosclerosis in the coronary arteries of patients effects endothelium-dependent vasodilator and vasoconstrictor responses. A program of research is proposed that utilizes new insights from the experimental laboratory to address three specific aims. The first will test the hypothesis that endothelial vasodilator dysfunction in human coronary arteries leads to constrictor hyperresponsiveness to catecholamines. The second specific aim will test the hypothesis that endothelium-derived constrictor factors (the polypeptide endothelin, as well as prostanoid factors) are secreted from human atherosclerotic arteries in inappropriately large amounts in response to stimuli known to cause enhanced vasoconstriction and thereby contribute to the development of myocardial ischemia. The third specific aim will examine in patients the concepts derived from experimental studies that aggressive lowering of cholesterol can improve endothelium-dependent vascular function apart from important changes in vessel luminal size. These studies should expand our knowledge of the mechanisms and treatment of abnormal constriction of human coronary arteries, and facilitate clinical attempts to control active ischemia.