DNA MODIFICATIONS--I COMPOUNDS AS BIOMARKERS OF AGING

DNA 修饰——I 化合物作为衰老生物标志物

• 批准号: 3119031
• 负责人: KURT RANDERATH
• 金额: $ 9.16万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-04-01 至 1993-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3119031
• 关键词: DNA; aging; animal old age; caloric dietary content; chemical addition; genetic strain; kidney; laboratory rat; leukocytes; liver; mature animal; noninvasive diagnosis; nutrition of aging; nutrition related tag; physiology; radioassay; thin layer chromatography

We will apply a 32P-labeling technique to investigate age- dependent DNA modifications, termed I-compounds, as potential biomarkers of aging. I-compounds are recently discovered DNA adduct-like DNA derivatives that were found in our laboratory to increase with age in rodent tissues. I-compound profiles are strongly dependent on tissue, species, and (to a lesser extent) sex of animals. They appear to show little inter-animal variation, both qualitatively and quantitatively, in animals of the same age. I-compounds may thus provide a quantitative biomarker of aging that would be useful in the biomonitoring of humans if measured in easily accessible cells or tissues. We will test this hypothesis using rats of the NIA/NCTR biomarker research colony, focusing on DNA of white blood cells and skin, i.e. tissues available from humans with a minimum degree of invasiveness. White blood cell and skin DNA will be isolated from individual female and male Fischer 344 (F344), Brown-Norway (BN), and F344 x BN hybrid rats of different ages, from both ad libitum fed and dietary restricted groups. There will be 8 age points: 4, 6, 8, 10, 12, 16, 20, and 24 months and 6 rats per point. In addition, liver and kidney DNA will be isolated from pooled tissue samples of the biomarker research colony rats at each of the age points. Levels and patterns of I-compounds will be analyzed by a 32P- postlabeling assay for covalent DNA modifications. A total of 1536 DNA specimens will be examined over the 5-year course of the project. Analysis of liver and kidney DNA of the rats will show whether I-compound changes in internal organs parallel those in white blood cells and skin. At each age, a sufficient number of analyses will be conducted to assess this approach in terms of its reproducibility, sensitivity, significance of rate of change, non-lethality (e.g., use of white blood cells), potential relevance to human aging, and technical requirements. This research will provide a definitive answer to the question as to whether the measurement of I-compounds will provide a useful non-invasive method for biomonitoring of aging.

我们将应用 32P 标记技术来调查年龄- 依赖DNA修饰，称为I-化合物，作为潜在的 衰老的生物标志物。 I-化合物是最近发现的DNA 我们实验室发现的类似加合物的 DNA 衍生物 啮齿动物组织中随着年龄的增长而增加。 I-化合物概况为 强烈依赖于组织、物种和（较小程度上）性别 的动物。 它们似乎表现出很小的动物间差异， 在同龄动物中，无论是质量还是数量。 I-化合物因此可以提供衰老的定量生物标志物 如果测量的话，这将有助于人类的生物监测 在容易接近的细胞或组织中。 我们将检验这个假设 使用 NIA/NCTR 生物标志物研究群体的大鼠，重点关注 白细胞和皮肤（即可从以下来源获得的组织）的 DNA 人类具有最小程度的侵入性。 将从个体中分离出白细胞和皮肤 DNA 雌性和雄性 Fischer 344 (F344)、Brown-Norway (BN) 和 F344 x 不同年龄的 BN 杂交大鼠，来自随意喂养和 饮食受限人群。 将有 8 个年龄点：4、6、8、10， 12、16、20 和 24 个月，每点 6 只大鼠。 此外，肝 肾脏 DNA 将从合并的组织样本中分离出来 生物标志物研究每个年龄点的群体大鼠。 级别 I-化合物的模式将通过 32P- 进行分析 共价 DNA 修饰的标记后测定。 总共有 将在 5 年的时间里检查 1536 个 DNA 样本 该项目。 对大鼠的肝脏和肾脏 DNA 进行分析 显示I-化合物在内脏器官中的变化是否平行 白细胞和皮肤中的那些。 每个年龄段都有足够的 将进行大量分析来评估这种方法 就其再现性、灵敏度、比率的显着性而言 变化、非致命性（例如，使用白细胞）、潜力 与人类衰老的相关性和技术要求。 这 研究将为这个问题提供明确的答案 I-化合物的测量是否会提供有用的 衰老生物监测的非侵入性方法。