A Novel p16INK4a Reporter System to Assess Aging In Vivo

一种评估体内衰老的新型 p16INK4a 报告系统

• 批准号: 8609538
• 负责人: Christin E Burd
• 金额: $ 24.18万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8609538
• 关键词: Address; Age; Age of Onset; Aging; Aging-Related Process; Alleles; American; Animals; Autoimmunity; Behavior Therapy; Biological; Biological Aging; Biological Assay; Biological Markers; Biological Models; Bioluminescence; CDKN2A gene; Caloric Restriction; Cardiovascular Diseases; Cell Aging; DNA Damage; Data; Detection; Development; Disease; Elderly; Embryo; Environmental Risk Factor; Event; Exercise; Fatty acid glycerol esters; Fibroblasts; Firefly Luciferases; Gene Expression Profile; Goals; Health; Human; In Vitro; Incidence; Individual; Intrinsic factor; Ionizing radiation; Kinetics; Knock-in Mouse; Life; Link; Longevity; Luciferases; Malignant Neoplasms; Measures; Methods; Modeling; Moderate Exercise; Molecular; Monitor; Mus; Nature; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Organ; Organ Specificity; Pancreas; Physiological; Population; Premature aging syndrome; Primates; Process; Property; Reading; Regulation; Reporter; Research; Rodent; Running; Specificity; System; Testing; Time; Tissues; Western Blotting; Work; abstracting; age related; anti aging; cell age; cell type; chromatin immunoprecipitation; chromatin modification; design; diet and exercise; dietary restriction; human subject; in vivo; insight; mouse model; novel; promoter; senescence

6. Project Summary/Abstract: The incidence of age-related diseases continues to rise as the number of Americans over the age of 65 grows. As a result, research is now focused on discovering methods to promote longevity. Although few molecular indicators of biological age have been indentified, we and others have recently shown that p16INK4a serves a robust and accurate marker of mammalian aging. Induction of p16INK4a correlates directly with chronological age in rodents and can be slowed by anti-aging strategies such as caloric restriction. In addition, our preliminary data show that p16INK4a levels are decreased by moderate exercise in healthy human subjects. Despite these data, the mechanisms by which lifestyle modification promotes longevity remain largely undefined. Herein, I will exploit the unique properties of p16INK4a as an aging biomarker to assess the tissue- specificity of anti-aging strategies. To do this, I have developed a novel knockin reporter allele, p16-LUC, which expresses firefly luciferase under control of the endogenous p16INK4a promoter. Importantly, my preliminary data show that induction of this allele correlates with cellular senescence in vitro and can be visualized in living animals. Using these mice I plan to address the following specific aims: 1) Characterize the p16- LUC allele under conditions relevant to the mammalian aging process, 2) Investigate the influence of diet and exercise on the induction of p16INK4a, 3) Determine the time- dependent and organ-specific effects of diet and exercise on p16INK4a promoter occupancy.

6. 项目概要/摘要： 随着美国人数量的增加，与年龄相关的疾病的发病率持续上升 65岁以上增长。因此，现在的研究重点是发现方法 促进长寿。尽管生物年龄的分子指标还很少 经鉴定，我们和其他人最近表明 p16INK4a 具有强大且 哺乳动物衰老的准确标记。 p16INK4a 的诱导与 啮齿类动物的实际年龄，可以通过热量等抗衰老策略来延缓 限制。此外，我们的初步数据显示 p16INK4a 水平降低了 健康人类受试者进行适度运动。尽管有这些数据，但该机制 哪种生活方式的改变可以促进长寿仍然很大程度上尚不明确。在此，我将 利用 p16INK4a 作为衰老生物标志物的独特特性来评估组织- 抗衰老策略的特异性。为此，我开发了一种新颖的敲击记者 等位基因，p16-LUC，在内源性基因的控制下表达萤火虫荧光素酶 p16INK4a 启动子。重要的是，我的初步数据表明该等位基因的诱导 与体外细胞衰老相关，并且可以在活体动物中观察到。 我计划使用这些小鼠来实现以下具体目标：1）表征 p16- LUC 等位基因在与哺乳动物衰老过程相关的条件下，2) 研究 饮食和运动对 p16INK4a 诱导的影响，3) 确定时间- 饮食和运动对 p16INK4a 启动子的依赖性和器官特异性影响 占用。