AGE RELATED DEGENERATION

与年龄有关的退化

基本信息

批准号：
2866834
负责人：
Charles J Epstein
金额：
$ 60.29万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-09-20 至 2003-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2866834
关键词：
DNA damage aging cerebral degeneration disease /disorder model enzyme activity free radical oxygen free radical scavengers gene mutation genetic models genetic strain genetically modified animals laboratory mouse mitochondrial DNA neural degeneration superoxide dismutase transfection

项目摘要

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.

该项目的目标是确定变更的影响氧自由基代谢酶的平衡对衰老的影响过程。人们对无氧的作用非常感兴趣自由基可能在衰老过程以及衰老过程中发挥作用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力方法是扰乱处理氧自由基的系统，以及许多这样做的方法已被使用。转基因动物已用于此目的并被发现是一种特别有效的生产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。在这个提案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 (CuZnSOD) 和/或 MnSOD 活性对年龄相关的影响并引起大脑、心脏和其他器官的退行性变化，线粒体和核 DNA 突变的积累以及氧化应激的其他生物标志物以及各个方面线粒体功能。将特别关注自由基失衡对中枢神经系统的影响，以及学习和记忆以及大脑功能的年龄依赖性变化将评估基础前脑胆碱能系统。待成为的动物研究将包括过度表达 CuZnSOD 或 MnSOD、完全缺乏 CuZnSOD 的突变小鼠和缺乏 CuZnSOD 的小鼠或 MnSOD 水平极低。改造小鼠以使其具有低水平 MnSOD 活性，四环素调节的转基因反式激活因子系统将被使用并适应以产生低表达 MnSOD 基因。转基因小鼠品系将被在这个项目中生成的，以及那些已经存在的，构成一组独特的模型动物，这将使研究对与年龄相关的细胞内退行性过程的影响 SOD 活性从缺失到显着升高，从而导致超氧化物水平的改变。