AGE RELATED DEGENERATION

这个项目的目标是确定改建的影响 氧自由基代谢酶在衰老过程中的平衡 进程。人们对氧自由基的作用相当感兴趣 自由基可能在衰老过程中起作用，也可能在 许多类型的退化过程和对创伤的反应。一个 调查这些问题的有效方法是扰乱 用于处理氧自由基的系统以及许多这样做的方法 已经被利用了。转基因动物已被用于这一目的 已经被发现是一种特别有效的生产方法 所需的扰动类型，因为既有可重复性 所产生的变化及其随时间的稳定性。在本建议书中 描述了一系列关于改变CuZn-的影响的研究。 超氧化物歧化酶和/或锰超氧化物歧化酶活性与年龄的关系 并导致大脑、心脏和其他器官的退行性变化， 关于线粒体和核DNA突变的积累以及 氧化应激的其他生物标志物，以及在 线粒体功能。我们会特别注意 自由基失衡对中枢神经系统的影响，以及 学习记忆和脑功能的年龄相关性变化 将评估基底前脑胆碱能系统。未来的动物 研究将包括过表达铜锌超氧化物歧化酶或 铜锌超氧化物歧化酶完全缺失的突变小鼠和缺失的小鼠 或者是非常低的MnSOD水平。为了设计出低水平的小鼠 四环素调控的转基因反式激活因子MnSOD活性 系统将被使用，并将被调整为产生低表达的 MnSOD的基因。转基因小鼠的品系将是 在这个项目中生成的，以及已经存在的那些， 构成了一套独特的模型动物，这将使我们有可能 对细胞内与年龄相关的退变过程的影响 从缺席到大幅提高的超氧化物歧化酶活动，以及 由此产生的超氧化物水平的变化。

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.