POLY (ADP-RIBOSE) SYNTHETASE AND REPERFUSION INJURY

描述(改编自申请人的摘要)：当前提案 旨在研究核酶多聚(ADP-核糖)的作用 合成酶(PARs)在心肌缺血再灌注病理生理中的作用 受伤。首先，将确定药物抑制是否 PARS改善细胞能量紊乱和功能障碍 心肌缺血再灌注损伤过程中的变化。这一假设 将在体外灌流的心脏制剂和小鼠模型中进行测试 应用DNA相关技术研究心肌缺血再灌注损伤 链断裂、PARS活性、细胞内能量学和心肌 伸缩性。PARs将受到药物和分子的抑制 生物学方法。对于药理学方法，3-氨基苯甲酰胺， 将使用一种典型的PAR抑制剂。此外，回应将是 比较野生型小鼠和缺乏基因敲除小鼠的心脏 功能性PARS酶。羟基自由基的相对贡献 过氧亚硝酸根与过氧亚硝酸根对心肌PARs激活的影响 还将使用药物来解决缺血再灌注问题 抑制剂。首席调查员还将调查 血管内皮细胞在心肌再灌注损伤中的作用 对这些变化的分析。

DESCRIPTION (adapted from the applicant's abstract): The current proposal is aimed at investigating the role of the nuclear enzyme poly (ADP-ribose) synthetase (PARS) in the pathophysiology of myocardial ischemia-reperfusion injury. First, it will be established whether pharmacological inhibition of PARS ameliorates the cellular energetic derangement and the functional alterations during myocardial ischemia-reperfusion injury. This hypothesis will be tested in in vitro perfused heart preparations and in a mouse model of myocardial ischemia-reperfusion injury by correlating DNA strand-breakage, PARS activity, intracellular energetics, and myocardial contractility. PARS will be inhibited by pharmacological and molecular biological approaches. For the pharmacological approach, 3-aminobenzamide, a prototypical inhibitor of PARS will be used. Moreover, responses will be compared in hearts of wild-type mice and of knock-out mice lacking the functional PARS enzyme. The relative contribution of hydroxyl radical versus peroxynitrite in the activation of PARS in myocardial ischemia-reperfusion will also be addressed using pharmacological inhibitors. The principal investigator will also investigate the changes in endothelial function during myocardial reperfusion injury, and the role of PARS in these changes.