AGE RELATED DEGENERATION

本项目的目标是确定改建的影响 氧自由基代谢酶平衡对衰老的影响 过程 人们对无氧的作用很感兴趣， 自由基可能在衰老过程中发挥作用，以及在 许多类型的退化过程和对创伤的反应。 一 调查这些问题的有力方法是扰乱 用于处理氧自由基的系统，以及许多这样做的方法， 用了 转基因动物已被用于这一目的 并且已经发现这是一种特别有效的方法， 所需的扰动类型，因为再现性 所产生的变化及其随时间的稳定性。 本提案中 描述了一系列研究的影响，改变铜锌- 超氧化物歧化酶（CuZnSOD）和/或MnSOD活性对年龄相关的 并导致大脑、心脏和其他器官的退行性变化， 线粒体和核DNA突变的积累， 氧化应激的其他生物标志物，以及 线粒体功能 将特别注意 自由基失衡对中枢神经系统的影响，以及 年龄依赖性的学习和记忆的变化， 将评估基底前脑胆碱能系统。 未来的动物 研究将包括过表达CuZnSOD或 MnSOD、完全缺乏CuZnSOD的突变小鼠和缺乏CuZnSOD的小鼠 或极低水平的MnSOD。 为了让老鼠体内的 四环素调控的转基因反式激活因子MnSOD活性 系统将被使用，并将被调整，以产生低表达的 MnSOD基因。 这些转基因小鼠的品系， 在这个项目中产生的，沿着那些已经存在的， 构成了一套独特的模型动物， 研究对细胞内与年龄相关的退行性过程的影响， SOD活性从缺失到显著升高， 导致超氧化物水平的改变。

The objective of this project is to determine the effects of alterations in the balance of oxygen free radical metabolizing enzymes on the aging process. There is considerable interest in the role which oxygen free radicals may play in the aging process, as well as in the genesis of many types of degenerative processes and reactions to trauma. A powerful approach to the investigation of these issues is to perturb the system for handling oxygen free radicals, and many ways of doing so have been used. Genetically modified animals have been used for this purpose and have been found to be a particularly powerful method for producing the types of perturbations desired, because of both the reproducibility of the changes produced and their stability over time. In this proposal are described a series of studies of the effects of altered CuZn- superoxide dismutase (CuZnSOD) and/or MnSOD activities on age-related and induced degenerative changes in the brain, heart, and other organs, on the accumulation of mitochondrial and nuclear DNA mutations and of other biomarkers of oxidative stress, and on various aspects of mitochondrial function. Particular attention will be paid to the effects of free radical imbalance on the central nervous system, and age-dependent changes in learning and memory and in the function of the basal forebrain cholinergic system will be assessed. The animals to be studied will include transgenic mice overexpressing either CuZnSOD or MnSOD, mutant mice completely lacking in CuZnSOD, and mice with absent or very low levels of MnSOD. To engineer the mice with low levels of MnSOD activity, the tetracycline-regulated transgenic transactivator system will be used and will be adapted to produce low expression of the gene for MnSOD. The strains of genetically altered mice which will be generated in this project, along with those which already exist, constitute a unique set of model animals which will make it possible to study the effects on age-related degenerative processes of intracellular SOD activities ranging from absent to greatly elevated and of the resulting alterations of superoxide levels.