ENDOTHELIAL DYSFUNCTION OF HUMAN CORONARY ARTERIOLES

描述 (根据申请人的摘要改编)应聘者最近完成了 心血管疾病研究员，目前是全日制大三学生 加州大学内科系教员 爱荷华州。他在冠状动脉生理学的基础研究方面取得了成功 并显示出获得独立地位的希望。建议进行的研究 将在资金充裕和成熟的实验室中进行， 贝弗利·戴维森博士和大卫·古特曼博士在 爱荷华大学。为他提供的环境支持和设施 都是杰出的。拟议的研究将为申请者提供培训 在细胞和分子生物学方面，这将使他能够将这些 并加强他的生理学研究。培训和经验 这份提案中概述的内容将在申请人的目标中发挥不可估量的作用 作为一名血管生物学领域的学术心脏病专家，具有竞争力。 有研究表明，1)动脉粥样硬化损害了 人冠状动脉微循环的内皮依赖性血管扩张作用 氧化应激增加的结果，以及血管功能障碍 通过内皮细胞超氧化物歧化酶的过度表达而改善。这个 建议在其对病变的人类冠状动脉微血管和 基因转移在纠正临床重要血管疾病中的应用 异常现象。离体房小动脉或室小动脉，新鲜获取于 将准备好体外循环或心脏移植的时间 用于内径的视频显微镜检查。急性呼吸道感染的影响 (邻苯三酚)与慢性(动脉粥样硬化)氧化应激 将进行血管内皮依赖性扩张试验。精神障碍的发病机制 动脉粥样硬化中的血管扩张将通过检查 血管平滑肌对一氧化氮和非一氧化氮的敏感性 刺激，评估血管收缩前列腺素的作用，并评估 动脉粥样硬化时细胞内超氧化物歧化酶水平降低。候选人将会 还要确定过量生产超氧化物歧化酶是否具有保护性 抗氧自由基介导的功能障碍。体外培养的腺病毒 人类三种超氧化物歧化酶亚型(锰、铜-锌或 细胞外)，每个都有特定的细胞定位 来自动脉粥样硬化患者和非动脉粥样硬化患者的小动脉。功能性 将检测这些血管内皮血管扩张的变化。 申请人提供的初步数据支持建议的可行性。 学习。血管生物学的物种差异及其在动物中的局限性 疾病模型强调了进行这些研究的重要性。 (摘要结束)

DESCRIPTION (Adapted from applicant's abstract) The candidate has recently completed a fellowship in Cardiovascular Disease and is currently a full-time junior faculty member in the Department of Internal Medicine at the University of Iowa. He has demonstrated success in basic research of coronary physiology and shows promise of attaining independent status. The proposed studies will be performed in well-funded and established laboratories under the co-sponsorship of Drs. Beverly Davidson and David Gutterman at the University of Iowa. Environmental support and facilities available to him are outstanding. The proposed studies will provide the applicant training in cellular and molecular biology which will allow him to integrate these disciplines and extend his physiologic studies. The training and experience outlined in this proposal will be invaluable in the applicant's goal to be competitive as an academic cardiologist in the field of vascular biology. There are studies of the hypotheses that 1) atherosclerosis impairs endothelium-dependent vasodilation of the human coronary microcirculation as a result of increased oxidative stress, and that 2) vascular dysfunction can be improved by endothelial cell overexpression of superoxide dismutase. The proposal is novel in its study of diseased human coronary microvessels and the use of gene transfer to correct clinically important vascular abnormalities. Isolated atrial or ventricular arterioles, obtained fresh at the time of cardio-pulmonary bypass or cardiac transplant, will be prepared for videomicroscopic examination of internal diameter. The effect of acute (pyrogallol) and chronic (atherosclerosis) oxidative stress on endothelium-dependent dilation will be tested. The mechanism of impaired vasodilation in atherosclerosis will be determined by examining the sensitivity of vascular smooth muscle to nitric oxide and non-nitric oxide stimuli, evaluate the role of vasoconstrictor prostanoids, and assess for decreased cellular levels of SOD in atherosclerosis. The candidate will also determine whether overproduction of superoxide dismutase is protective against reactive oxygen species mediated dysfunction. In-vitro adenoviral transfer of genes for three human SOD isoforms (manganese, copper-zinc, or extracellular), each with specific cellular localization, will be performed in arterioles from patients with and without atherosclerosis. Functional changes of endothelial vasodilation in these vessels will be tested. Preliminary data by the applicant support the feasibility of the proposed studies. Species differences of vascular biology and limitations in animal models of disease underscore the importance of performing these studies. (End of abstract)