OXIDANTS IN MYOCARDIAL PRECONDITIONING

心肌预处理中的氧化剂

• 批准号: 2450768
• 负责人: Terry L. Vanden Hoek
• 金额: $ 8.26万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-15 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2450768
• 关键词: adenosine; antioxidants; biological signal transduction; chemoprevention; cytotoxicity; enzyme activity; free radical oxygen; heart cell; intracellular transport; muscle cells; myocardial ischemia /hypoxia; nitric oxide; nitric oxide synthase; oxidative stress; perfusion; potassium channel; protein kinase; tissue /cell culture

DESCRIPTION (Adapted from applicants' abstract) This application intends to complement the candidate's work in Emergency Medicine and previous Cellular research. Dr. Vanden Hoek is board certified in Emergency Medicine, appointed as Assistant Professor in the Section of Emergency Medicine, Department of Medicine at the University of Chicago. He has served as the site primary investigator in a multicenter trial regarding the rapid diagnosis of ischemic heart disease. His clinical and research backgrounds logically extend into asking how the ischemic heart can be better protected at the cellular level. Answers could improve our clinical treatment of myocardial infarction and other ischemic diseases, leading causes of death and disability. Preliminary work shows that preconditioning in cardiomyocytes, whereby brief hypoxia protects against subsequent ischemia/reperfusion injury, is mediated by reactive oxygen species (ROS). Intracellular fluorescent probes sensitive to these ROS suggest that preconditioning is initiated by ROS signaling during brief hypoxia. Subsequently, the severe ROS generation and injury typically seen during ischemia/reperfusion is attenuated by preconditioning. These protective effects are reversed when nitric oxide (NO) formation is inhibited, implicating a role for NO in preconditioning. Given these results, the applicant will (a) test if low levels of oxidants induce precondition, (b) test whether mediators of preconditioning such as adenosine, protein kinase activation, or potassium channel opening attenuate oxidant injury, and (c) will examine the role of NO in this oxidant protection. Perfused cardiomyocytes have proven useful for the study of oxidant injury and preconditioning, two ideas central to this proposal. These cells can be monitored for cell contraction, intracellular oxidants and antioxidant defenses, and cell death in a system free of confounding factors such as vascular flow, humoral and neural factors. Proposed agonists and antagonists of preconditioning can be tested for their effect on oxidant stress and injury, and levels of nitric oxide can be easily modified. The candidate has extensive physical and academic support at the University of Chicago, with his own dedicated lab space and established ongoing relationships with two senior mentors keenly interested in seeing his work succeed. In addition, he is an invited member of a faculty workgroup, The Oxidative Stress and Signaling Workgroup, which meets monthly and has already helped his growth as a reactive oxygen and cellular investigator. (End of Abstract)

描述 （改编自申请人的摘要）此申请打算补充 候选人在急诊医学和先前的细胞研究中的工作。 范登·霍克（Vanden Hoek）博士是急诊医学董事会认证，被任命为 急诊医学部门的助理教授 芝加哥大学的医学。 他曾担任主要网站 研究人员在一项有关快速诊断的多中心试验中 缺血性心脏病。 他的临床和研究背景在逻辑上 延伸到询问如何更好地保护缺血性心脏 细胞水平。 答案可以改善我们对心肌的临床治疗 梗塞和其他缺血性疾病，导致死亡的主要原因和 残疾。 初步工作表明心肌细胞的预处理 缺氧可预防随后的缺血/再灌注损伤，介导 通过活性氧（ROS）。 细胞内荧光探针 对这些ROS敏感的表明，预处理是由ROS启动的 短暂缺氧期间的信号传导。 随后，严重的ROS产生和 通常在缺血/再灌注期间看到的伤害被削弱 预处理。 一氧化氮时，这些保护效果会逆转 （NO）形成被抑制，暗示了NO在预处理中的作用。 鉴于这些结果，申请人将（a）测试如果低水平的氧化剂 诱导前提条件，（b）测试是否有前提的调解人（例如 腺苷，蛋白激酶激活或钾通道开口 氧化剂损伤，（c）将检查NO在该氧化剂中的作用 保护。 灌注的心肌细胞已被证明对研究 氧化剂损伤和预处理，这是该提案的两个核心。 可以监测这些细胞的细胞收缩，细胞内氧化剂 和抗氧化剂防御和细胞死亡，无混杂的系统 血管流，体液和神经因素等因素。 建议的 可以测试激动剂和拮抗剂的作用 在氧化应激和损伤上，一氧化氮的水平很容易被 修改的。 候选人在大学拥有广泛的身体和学术支持 芝加哥，拥有自己的专门实验室空间，并建立了持续的 与两位高级导师的关系，对看他的工作感兴趣 成功。 此外，他是教师工作组的受邀成员， 氧化应激和信号传导工作组，每月满足并且具有 已经帮助他作为活性氧和细胞研究者的生长。 （抽象的结尾）