Novel Age-Dependent DNA Modifications

新型年龄依赖性 DNA 修饰

• 批准号: 10428487
• 负责人: Peter C Dedon
• 金额: $ 40.41万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10428487
• 关键词: Affect; Age; Age of Onset; Aging; Biochemistry; Biology; Birds; Brain; Caloric Restriction; Cells; Chronology; Classification; Communities; DNA; DNA Adducts; DNA Damage; DNA Methylation; DNA Modification Process; DNA Repair; DNA lesion; Data; Development; Diet; Disease; Epidemic; Epigenetic Process; Event; FRAP1 gene; Gene Expression; Genes; Genetic; Genetic Materials; Growth; Isotopes; Lead; Lesion; Life; Life Expectancy; Link; Longevity; Malignant Neoplasms; Mass Spectrum Analysis; Measurement; Measures; Metabolic; Metabolic Control; Metabolic Pathway; Metabolism; Methods; Methylation; Mitotic; Molecular; Onset of illness; Oxidative Stress; Pathway interactions; Process; Resolution; Scientist; Structure; Techniques; Technology; Telomere Shortening; Testing; Time; Tissues; adduct; age related; base; biological systems; cigarette smoke; circadian pacemaker; disease phenotype; epigenetic marker; epigenome; experimental study; human tissue; innovation; insulin signaling; novel; oxidation; promoter; repaired; telomere; theories

Life expectancy has increased dramatically over the last century, bringing world-wide epidemics of age- related diseases. Although there have been many theories proposed for aging, the mechanisms by which cells record time or mark time are largely unknown. Recent developments in the field of epigenetics have shown that methylation in specific regions closely correlates to age. However, the epigenome is a malleable molecular product that is regulated by many external factors. Additional mechanisms by which cells can track long periods of time chronologically remain undefined. We propose that specific DNA damage products can accumulate over time, and that this DNA damage is affected by metabolic events. Identifying specific DNA adducts that accumulate at later stages of life would open a new view of disease onset that directly interfaces genetics and metabolism. Although the concept of time tracking through DNA damage is not new, we now have the technology to measure specific DNA lesions at high resolution and sensitivity, and to discover new lesions--allowing a rigorous and quantitative test of this hypothesis. In fact, our preliminary data reveal at least 3 as-yet-unidentified DNA products in DNA of old mammalian brains that are present in substantially higher quantities compared in DNA of young mammalian brains. Identification of these and other DNA adducts that accumulate with aging would be broadly groundbreaking, but particularly for understanding why diverse diseases strike at specific times of life. In the experiments in this project, we will identify the 3 DNA products that accumulate in mammalian brains with aging. We will also discover new DNA products in other tissues with aging. We will synthesize the unknown DNA molecules and use isotope dilution mass spectrometry to quantitate the new DNA molecules in any biological system. Performing this biochemistry will open the door for major downstream questions. Do these new DNA molecules escape DNA repair? Are they mutagenic, or do they affect gene expression? What metabolic biochemistry regulates the formation of these age-related DNA molecules? Once we define these new DNA molecules as “long term clocks”, and we provide the structures and rigorous measurement methods to the scientific community, scientists can begin to ask interesting questions about whether these molecules could function in biological systems as “alarm clocks”.

上个世纪，预期寿命急剧增加，带来了世界范围内的老龄化流行病- 相关疾病。尽管有许多关于衰老的理论，但细胞衰老的机制 记录时间或标记时间基本上是未知的。表观遗传学领域的最新进展表明， 特定区域的甲基化与年龄密切相关。然而，表观基因组是一种可塑性分子， 这是一种受许多外部因素影响的产品。细胞可以跟踪长时间的其他机制 按时间顺序排列的时间段仍未确定。 我们认为，特定的DNA损伤产物可以随着时间的推移而积累， 会受到代谢事件的影响识别在生命后期积累的特定DNA加合物， 开辟了一个新的观点，疾病发作，直接接口遗传学和代谢。的概念虽然 通过DNA损伤进行时间跟踪并不新鲜，我们现在已经有了测量特定DNA损伤的技术 以高分辨率和灵敏度，并发现新的病变-允许对此进行严格的定量测试。 假说.事实上，我们的初步数据显示，在老年人的DNA中至少有3种尚未鉴定的DNA产物， 哺乳动物大脑中存在的数量大大高于年轻哺乳动物的DNA 大脑鉴定这些和其他随着衰老而积累的DNA加合物将是广泛的 这是一项开创性的研究，尤其是对于理解为什么不同的疾病会在生命的特定时期发生。 在本项目的实验中，我们将鉴定在哺乳动物中积累的3种DNA产物， 大脑老化我们还将在其他组织中发现新的DNA产物。我们将合成 未知的DNA分子，并使用同位素稀释质谱法定量新的DNA分子， 任何生物系统。进行这种生物化学将为主要的下游问题打开大门。做 这些新的DNA分子逃脱了DNA修复它们是致突变的，还是影响基因表达？什么 代谢生物化学调节这些与年龄相关的DNA分子的形成？一旦我们定义了这些 新的DNA分子作为“长期时钟”，我们提供了结构和严格的测量方法， 对于科学界来说，科学家们可以开始提出一些有趣的问题， 在生物系统中可以起到“闹钟”的作用。