OXIDATIVE DNA DAMAGE, TRANSCRIPTION, REPAIR AND AGING

一段时间以来，累积的氧化损伤被认为是细胞衰老的标志。此外，各种生物体的寿命已被证明与其代谢率成反比，并与累积的氧化DNA损伤直接相关。这项研究的长期目标是研究氧化损伤的DNA在衰老过程中所起的作用。由于DNA是控制所有细胞功能的中心分子，因此持续的未修复损伤可能会产生重要影响。累积的氧化性DNA损伤的一个重要后果是其对转录交易的潜在有害影响。众所周知，随着年龄的增长，活性氧的产生会增加。这些事实加上衰老细胞表现出去除氧化性DNA损伤能力降低的可能性，是一种假设的基础，即未修复的氧化性DNA损伤的积累对mRNA转录产生有害影响，从而降低细胞适应性并导致衰老。为了验证这一假设，我们将使用一个完善的复制性衰老模型系统、人类胎儿肺成纤维细胞和来自Werner和Cockayne综合征患者的成纤维细胞来检测氧化DNA损伤的转录能力、修复能力和修复状态。类似的研究将在培养的分化的人类神经细胞中进行。使用设计的实验方法，未修复的氧化DNA损伤、转录受损和修复能力丧失之间的直接关系可能与衰老过程直接相关。

Accumulated oxidative damage has been recognized for some time as a hallmark of aging cells. Also, the life span of a variety of organisms has been shown to be inversely proportional to their metabolic rates and directly related to accumulated oxidative DNA damage. The long-range goal of this research is to examine the role that oxidatively damaged DNA plays in the aging process. Since DNA is the central molecule controlling all cellular function, it is likely that sustained unrepaired damages will exert important effects. One important consequence of accumulated oxidative DNA damage is its potential deleterious effect on transcriptional transactions. It is well established that the production of reactive oxygen species increases during aging. These facts coupled with the possibility that aging cells exhibit a reduced capacity to remove oxidative DNA damage, are the basis for the hypothesis that the accumulation of unrepaired oxidative DNA damage exerts effects on deleterious effects on mRNA transcription that reduce cellular fitness and contribute to aging. To test this hypothesis, transcriptional capacity, repair capacity, and repair status for oxidative DNA damage will be examined using a well established replicative senescence model system, human fetal lung fibroblasts, and fibroblasts obtained from Werner and Cockayne syndrome patients. Similar studies will be done in differentiated human neuronal cells in culture. Using the experimental approaches designed, a direct relationship between unrepaired oxidative DNA damage, impaired transcription and loss of repair capacity could be directly linked to the aging process.