Investigation of developmental peroxide generation as an important lifespan-deter

发育性过氧化物生成作为重要的寿命阻止因素的研究

• 批准号: 8716042
• 负责人: Ursula H. Jakob
• 金额: $ 23.33万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8716042
• 关键词: Adult; Affect; Age; Aging; Animal Model; Animals; Antioxidants; Caenorhabditis elegans; Complex; Conflict (Psychology); Development; Devices; Environment; Event; Free Radicals; Gene Expression; Gene Expression Profile; Generations; Genetic; Growth and Development function; Homeostasis; Individual; Individuality; Insulin Signaling Pathway; Intervention; Invertebrates; Investigation; Larva; Life; Life Expectancy; Longevity; Mammals; Mediating; Metabolism; Microfluidics; Molecular Profiling; Monitor; Organism; Oxidants; Oxidation-Reduction; Pathology; Pathway interactions; Pattern; Peroxides; Phenotype; Physiological; Play; Population; Production; Proteins; Proteomics; Reactive Oxygen Species; Relative (related person); Resistance; Role; Second Messenger Systems; Signal Transduction; Signaling Molecule; Sorting - Cell Movement; Staging; Stress; System; Techniques; Testing; Time; Tissues; Transgenic Organisms; Variant; Work; age related; base; experience; genetic manipulation; in vivo; mutant; public health relevance; ratiometric; research study; second messenger; sensor; signal processing; theories; tool; young adult

DESCRIPTION (provided by applicant): Genetically and chronologically identical animals show surprisingly large variations in lifespan and random patterns of aging-related pathologies. This apparent randomness, a phenomenon known as stochasticity of aging, is thought to either result from stochastic accumulation of damage over the entire lifespan and/or from developmentally set regulatory signals, which affect lifespan early in life. Based on previous results from our lab, we will now test the hypothesis that large fluctuations in peroxide levels observed during the larval development of C. elegans trigger a chain of redox-controlled events that individualize lifespan, thereby contributing to the observed lifespan variability. Reactive oxygen species, such as peroxide, have long been postulated to contribute to the age-associated physiological decline in organisms. More recent studies, however, also revealed regulatory roles of reactive oxygen species as intracellular signaling molecules, positively affecting metabolism, growth and development. We have generated transgenic C. elegans, which express ratiometric peroxide sensor proteins. These sensor proteins allow us to determine and monitor in real- time and in live organisms the relative amount of endogenous peroxide produced at any defined point in their life. We have discovered that C. elegans accumulate high levels of peroxide early in life, that the ability to restore a reducing environmen upon entering adulthood appears to predict longevity, and that individuals with lower than average developmental peroxide levels show an extended lifespan. We will now use these peroxide sensor-expressing worms to correlate endogenous peroxide levels in individual C. elegans with their age-related phenotypes, stress resistance and lifespan. We will sort C. elegans according to their ROS levels in early development, investigate the gene expression profile associated with variable early-life peroxide levels and apply targeted redox-proteomic techniques to identify physiologically important redox sensitive target proteins. Our studies have therefore the clear potential to reveal when individuality arises and uncover the mechanism(s) by which developmentally produced reactive oxygen species determine lifespan.

描述（由申请人提供）：基因和时间顺序相同的动物在寿命和衰老相关病理的随机模式方面表现出惊人的巨大差异。这种明显的随机性，一种被称为衰老随机性的现象，被认为是由于整个生命周期中损伤的随机积累和/或发育过程中设定的调节信号造成的，这些信号会影响生命早期的寿命。根据我们实验室之前的结果，我们现在将测试以下假设：在线虫幼虫发育过程中观察到的过氧化物水平的大幅波动会触发一系列氧化还原控制事件，从而使寿命个体化，从而导致观察到的寿命变异。长期以来，人们一直认为活性氧（例如过氧化物）会导致生物体与年龄相关的生理衰退。然而，最近的研究还揭示了活性氧作为细胞内信号分子的调节作用，对新陈代谢、生长和发育产生积极影响。我们已经产生了转基因线虫，它表达比例过氧化物传感器蛋白。这些传感器蛋白使我们能够实时确定和监测活体生物体在其生命中任何特定时间点产生的内源过氧化物的相对量。我们发现，线虫在生命早期就积累了高水平的过氧化物，进入成年后恢复还原环境的能力似乎可以预测长寿，并且发育中过氧化物水平低于平均水平的个体显示出更长的寿命。我们现在将使用这些表达过氧化物传感器的蠕虫将个体秀丽隐杆线虫的内源过氧化物水平与其年龄相关的表型、应激抵抗力和寿命相关联。我们将根据早期发育中的 ROS 水平对线虫进行分类，研究与可变的早期过氧化物水平相关的基因表达谱，并应用靶向氧化还原蛋白质组技术来识别生理上重要的氧化还原敏感靶蛋白。因此，我们的研究具有明显的潜力，可以揭示个性何时产生，并揭示发育过程中产生的活性氧决定寿命的机制。