Oxidative stress and telomere maintenance in vivo

体内氧化应激和端粒维持

• 批准号: 6547872
• 负责人: ROBERT Anthony MARCINIAK
• 金额: $ 7.3万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6547872
• 关键词: DNA damage; DNA repair; RNA; Werner's syndrome; aging; animal breeding; chemical structure; enzyme activity; fluorescent in situ hybridization; gene mutation; genetically modified animals; genotype; laboratory mouse; oxidative stress; pathology; phenotype; superoxide dismutase; telomerase; telomere

The fundamental question in the biology of aging is-why do humans age? Many hypotheses have been put forth to answer this question. Among these are "oxidative damage theories" and "telomere theories" of aging. "Oxidative damage theories" state that aging occurs, in part, because normal biologic processes release reactive oxygen species that can damage cellular components. "Telomere theories" state that aging occurs that aging occurs in part, because telomere erosion occurs with each cell division in body cells that don't express telomerase. This loss of telomere sequence results in eventual cellular dysfunction. The research proposed is designed to clarify a simple question related to both of these "theories"does oxidative stress contribute to telomere sequence loss in vivo? This question attempts to unite "telomere theories" and "oxidative" damage theories" of aging-oxidative stress may influence age associated changes through an effect on the rate of telomere sequence loss. A seemingly simple question, it has not been simple to answer given the limitations of the individual experimental systems in which the question has been tested. Although a number of studies have demonstrated an accelerated rate of loss of telomeric repeats dependent on the level of exogenous oxidative stress in cells grown in tissue culture in vitro, the significance of these findings to processes occurring in vivo has been unclear. In the studies proposed herein, genetically manipulated mice will be used to test the significance of these findings in vivo. Mice cohorts heterozygous for the manganese superoxide dismutase gene and homozygous for telomerase RNA deletion will be bred, and rates of telomere loss in these cohorts relative to appropriate controls will be determined. By studying rates of telomere sequence loss in mice also lacking the Werner syndrome gene, the role of the Werner syndrome gene product in this process also will be determined.

衰老生物学的基本问题是人类为什么会衰老？为了回答这个问题，人们提出了许多假说。其中包括衰老的“氧化损伤理论”和“端粒理论”。“氧化损伤理论”指出，衰老的发生，部分原因是正常的生物过程释放活性氧，可以破坏细胞成分。“端粒理论”指出，衰老的发生是部分的，因为端粒的侵蚀发生在不表达端粒酶的体细胞的每次细胞分裂中。这种端粒序列的丢失最终导致细胞功能障碍。这项研究旨在澄清一个与这两种“理论”相关的简单问题，即氧化应激是否会导致体内端粒序列丢失？这个问题试图将衰老的“端粒理论”和“氧化”损伤理论”结合起来--氧化应激可能通过影响端粒序列丢失的速率来影响与年龄相关的变化。这是一个看似简单的问题，但由于测试该问题的单个实验系统的局限性，回答起来并不简单。虽然一些研究表明，端粒重复序列的损失速度加快依赖于外源性氧化应激水平在体外组织培养中生长的细胞，这些发现的意义在体内发生的过程一直不清楚。在本文提出的研究中，将使用遗传操作的小鼠来测试这些发现在体内的意义。将饲养锰超氧化物歧化酶基因杂合和端粒酶RNA缺失纯合的小鼠组群，并确定这些组群相对于适当对照的端粒丢失率。通过研究同样缺乏沃纳综合征基因的小鼠的端粒序列丢失率，沃纳综合征基因产物在这一过程中的作用也将被确定。