TRANSGENIC MICE FOR STUDY OF AGE RELATED CARDIAC DISEASE

描述（改编自申请人摘要）：申请人 假设活性氧是损伤的主要原因， 再灌注后的心肌缺血组织， 衰老心脏的恢复将通过过度表达一种或多种蛋白质而得到改善。 更多的抗氧化酶。 申请人表示，这 这一假设得到了先前观察结果的支持，即外源添加 各种抗氧化酶，如SOD和过氧化氢酶，提供 保护心脏免受缺血/再灌注损伤。 然而，在这方面， 酶疗法的有效性尚不清楚， 酶不能穿透自由基所在的心肌细胞， 制作。 为了鉴定限速抗氧化酶， 以有义构型携带SOD或过氧化氢酶转基因的小鼠 将被生成。 这些转基因被设计成 控制人β-肌动蛋白启动子以确保高水平转录 在动物的心中。 由于SOD和过氧化氢酶协同工作， 清除氧自由基，小鼠含有两种组合 转基因也将通过培育两只转基因创始小鼠来获得 每一个携带不同的转基因。 这些转基因的表达在 对照组和转基因小鼠在三个年龄（3，10和24岁）的心脏 将在酶活性水平下与其他酶一起沿着检查 抗氧化酶 改变的水平之间的关联 心肌抗氧化酶与缺血易感性/ 再灌注损伤将通过生理和生化两方面来定义 使用小鼠心脏灌注模型进行分析， 申请人的实验室

DESCRIPTION (adapted from the applicant's abstract): The applicant hypothesizes that reactive oxygen species are a major cause of injury in cardiac ischemic tissue following reperfusion and that the functional recovery of the aging heart will be improved by overexpressing one or more of the antioxidant enzymes. The applicant indicates that this hypothesis is supported by previous observations that exogenous addition of various antioxidant enzymes, such as SOD and catalase, provide protection to the heart against ischemia/reperfusion injury. However, the effectiveness of the enzyme therapy is not understood because these enzymes cannot penetrate the cardiac cells where the free radicals are produced. In order to identify the rate limiting antioxidant enzyme, mice carrying a SOD or catalase transgene at the sense configuration will be generated. These transgenes are being designed to be under the control of human b-actin promoter to insure high levels of transcription in the hearts of animals. Since SOD and catalase work in concert to remove oxygen free radicals, mice containing a combination of two transgenes will also be obtained by breeding two transgenic founder mice each bearing a different transgene. Expression of these transgenes in the hearts of control and transgenic mice at three ages (3, 10, and 24 month-old) will be examined at enzyme activity levels along with other antioxidant enzymes. Correlations between the altered levels of myocardial antioxidant enzymes and susceptibility to ischemia/ reperfusion injury will be defined by both physiological and biochemical analyses using the mouse heart perfusion model developed in the applicant's laboratory.