COLLAGEN BIOCHEMISTRY

胶原蛋白生物化学

• 批准号: 6334870
• 负责人: VINCENT MONNIER
• 金额: $ 31.28万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6334870
• 关键词: aging; animal old age; biomarker; collagen; crosslink; dietary restriction; female; gas chromatography mass spectrometry; glycation; histology; laboratory mouse; linkage mapping; molecular genetics; oxidation; oxidative stress; posttranslational modifications; protein metabolism

Project 5 will provide measurements of age-sensitive markers of collagen aging, metabolic status and oxidative stress int he group of 600 genotyped female UM-HET3 mice for studies of genetic linkage and biomarker validation. The test battery will also be performed on the 180 mice in Population 2, to see if mice selected for alleles that covey extended lifespan also show diminished level of protein glycation and oxidation. The set of tests includes measures of collagen glycation (furosine) and the glycoxidation products pentosidine and N/epsilon- carboxymethyl-lysine, whose rate of age-dependent increase is known from prior work to vary among inbred strains and to be sensitive to the age- retarding effects of calorie restriction. Data derived from Project 5 will confirm and extend pilot work suggesting that protein glycation and glycoxidation are under genetic control in the UM-HET3 mouse stock, and will show whether the genetic and non-genetic factors that influence these post-translational modifications also influence protein conformation (Project 4), affect the immune cells, muscle, and bone tissue (Projects 1, 2 and 3), and might be associated with individual differences in DNA sequence stability (Project 6). In addition, the data derived from Project 5 will permit a comprehensive evaluation of several indices of protein modification, including formation of methionine sulfoxide and the thermal stability of tail tendon collagen, a sensitive marker of collagen crosslinking. The relationships of these adducts to the other markers of metabolic state (pentosidine, furosine and CML), and their possible links to age- sensitive measures of immune, muscle, and bone function, will emerge from the combination of correlational and genetic analyses possible only within the context of a multi-component program.

项目5将测量600只基因型雌性UM-HET3小鼠的胶原老化、代谢状态和氧化应激的年龄敏感标志物，以研究遗传联系和生物标志物验证。该试验还将在第二种群的180只老鼠身上进行，以观察携带延长寿命等位基因的老鼠是否也会显示出蛋白质糖化和氧化水平的降低。这组测试包括胶原糖基化（糠氨酸）和糖氧化产物戊苷和N/epsilon-羧甲基赖氨酸的测量，从先前的工作中可以知道，其年龄依赖性增长的速度在自交菌株之间有所不同，并且对限制热量的年龄延迟效果很敏感。来自项目5的数据将证实和扩展试点工作，表明蛋白质糖基化和糖氧化在UM-HET3小鼠种群中受遗传控制，并将显示影响这些翻译后修饰的遗传和非遗传因素是否也影响蛋白质构象（项目4），影响免疫细胞、肌肉和骨组织（项目1、2和3），并可能与DNA序列稳定性的个体差异有关（项目6）。此外，来自Project 5的数据将允许对蛋白质修饰的几个指标进行综合评估，包括蛋氨酸亚砜的形成和尾腱胶原的热稳定性，这是胶原交联的敏感标记。这些加合物与代谢状态的其他标记物（戊苷、糠氨酸和CML）之间的关系，以及它们与免疫、肌肉和骨骼功能的年龄敏感指标之间的可能联系，将从相关性和遗传分析的结合中浮现出来，只有在多组分程序的背景下才有可能。