ENDOTHELIAL DYSFUNCTION OF HUMAN CORONARY ARTERIOLES

描述 （摘自申请人摘要）候选人最近完成了一项 在心血管疾病奖学金，目前是一个全职的初级 他是芝加哥大学内科系的一名教员， 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。 拟议的研究 将在资金充足的实验室进行， 贝弗利·戴维森博士和大卫·古特曼博士在 爱荷华州大学。 他可获得的环境支持和设施 非常出色 拟议的研究将为申请人提供培训 在细胞和分子生物学中， 学科和扩展他的生理学研究。 培训和经验 在此建议中概述的将是非常宝贵的申请人的目标是 在血管生物学领域作为一名学术心脏病专家具有竞争力。 有研究假设1）动脉粥样硬化损害 人冠状动脉微循环的内皮依赖性血管舒张 氧化应激增加的结果，2）血管功能障碍， 通过内皮细胞超氧化物歧化酶的过度表达来改善。 的 该提案在研究患病的人类冠状动脉微血管方面是新颖的， 使用基因转移来纠正临床上重要的血管 异常 分离的心房或心室小动脉，新鲜获取， 心肺转流或心脏移植的时间，将准备 用于内径的视频显微镜检查。 急性的影响 （邻苯三酚）和慢性（动脉粥样硬化）氧化应激对 将测试内皮依赖性扩张。 受损的机制 动脉粥样硬化中的血管舒张将通过检查 血管平滑肌对一氧化氮和非一氧化氮敏感性 刺激，评估血管收缩剂前列腺素类的作用，并评估 降低动脉粥样硬化中SOD的细胞水平。 候选人将 还可以确定超氧化物歧化酶的过度产生是否具有保护作用 对抗活性氧介导的功能障碍。 体外腺病毒 转移三种人类SOD同工型（锰，铜锌，或 细胞外），每种都具有特定的细胞定位， 动脉粥样硬化患者和非动脉粥样硬化患者的小动脉中。 功能 将测试这些血管中内皮血管舒张的变化。 申请人的初步数据支持拟议的可行性 问题研究 动物血管生物学的种属差异及其局限性 疾病模型强调了进行这些研究的重要性。 (End摘要）

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)