Novel Age-Dependent DNA Modifications

新型年龄依赖性 DNA 修饰

• 批准号: 9759753
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9759753
• 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”.

在过去的一个世纪里，人们的预期寿命大幅增加，带来了世界性的年龄流行病- 相关疾病。尽管已经提出了许多关于衰老的理论，但细胞 记录时间或标志时间在很大程度上是未知的。表观遗传学领域的最新发展表明 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的分子 受许多外部因素调节的产品。细胞可以跟踪Long的其他机制 按时间顺序排列的时间段仍未定义。 我们认为，特定的DNA损伤产物可以随着时间的推移而积累，这种DNA损伤 会受到代谢事件的影响。识别在生命后期积累的特定DNA加合物将 打开了一种疾病发病的新观点，它直接将遗传学和新陈代谢联系在一起。虽然这一概念 通过DNA损伤进行时间跟踪并不是什么新鲜事，我们现在已经有了测量特定DNA损伤的技术 在高分辨率和高灵敏度下，并发现新的损伤--允许对此进行严格的定量测试 假设。事实上，我们的初步数据显示，在老年人的DNA中，至少有3种尚未确定的DNA产物 与幼年哺乳动物的DNA相比，哺乳动物的大脑中的含量要高得多 大脑。对这些和其他随着年龄增长而积累的DNA加合物的鉴定将是广泛的 开创性的，但特别是为了理解为什么不同的疾病在生命的特定时期发作。 在这个项目的实验中，我们将鉴定在哺乳动物体内积累的3种dna产物。 大脑随着年龄的增长。随着年龄的增长，我们还将在其他组织中发现新的DNA产物。我们将会综合出 未知的DNA分子，并使用同位素稀释质谱仪对新的DNA分子进行定量 任何生物系统。进行这种生物化学将为下游的重大问题打开大门。做 这些新的DNA分子逃脱了DNA修复？它们是诱变的，还是会影响基因表达？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”，我们提供了其结构和严谨的测量方法。 对于科学界来说，科学家们可以开始问一些有趣的问题，关于这些分子 可以在生物系统中起到“闹钟”的作用。