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标记的技术来研究年龄 依赖性DNA修饰，称为I-Compound，为电势 衰老的生物标志物。 i-compounds最近发现了DNA 在我们的实验室中发现的类似加合物的DNA衍生物 啮齿动物组织的年龄增加。 i-compound配置文件是 强烈依赖组织，物种和（在较小程度上）性别 动物。 它们似乎显示出很少的动物间变化， 在定性和定量上，在同一年龄的动物中。 因此，I-Compounds可能会提供衰老的定量生物标志物 如果测量 在易于进入的细胞或组织中。 我们将检验这个假设 使用NIA/NCTR生物标志物研究殖民地的大鼠 在白细胞和皮肤的DNA上，即可从 人类具有最小的侵入性。 白细胞和皮肤DNA将从个体中隔离 雌性和男性Fischer 344（F344），棕色 - 诺威（BN）和F344 X BN杂种大鼠来自不同年龄的大鼠。 饮食限制组。 将有8个年龄点：4、6、8、10， 每点12、16、20和24个月和6只大鼠。 另外，肝脏 和肾脏DNA将从合并的组织样品中分离出来 生物标志物研究殖民地大鼠在每个年龄点。 水平 I-Compound的模式将通过32p-分析 用于共价DNA修饰的标签测定。 总共 1536 DNA标本将在5年的课程中检查 项目。 大鼠肝脏和肾脏DNA的分析将 显示i-compound是否在内部器官中发生变化 白细胞和皮肤中的人。 在每个年龄，一个足够的 将进行分析数量以评估这种方法 其可重复性，灵敏度，速率的重要性 变化，非杀伤性（例如使用白细胞），潜力 与人类衰老和技术要求有关。 这 研究将为有关的问题提供明确的答案 I-Compound的测量是否会提供有用的 衰老生物监测的非侵入性方法。