COLLAGEN BIOCHEMISTRY

胶原蛋白生物化学

• 批准号: 6458990
• 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: 2001
• 资助国家: 美国
• 起止时间: 2001-06-05 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6458990
• 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 将在 600 只基因型雌性 UM-HET3 小鼠组中提供胶原蛋白老化、代谢状态和氧化应激的年龄敏感标记物的测量，用于遗传连锁和生物标记物验证的研究。该测试组还将在种群 2 中的 180 只小鼠上进行，以观察选择具有延长寿命的等位基因的小鼠是否也表现出蛋白质糖化和氧化水平降低。这组测试包括胶原蛋白糖化（呋喃）和糖氧化产物戊糖苷和N/ε-羧甲基-赖氨酸的测量，从先前的工作中已知其年龄依赖性增加率在近交系之间存在差异，并且对热量限制的延缓衰老作用敏感。来自项目 5 的数据将证实并扩展试点工作，表明 UM-HET3 小鼠中蛋白质糖化和糖氧化受到遗传控制，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相关 （项目 6）。此外，项目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蛋白的热稳定性，尾腱胶原蛋白是胶原蛋白交联的敏感标记。这些加合物与其他代谢状态标志物（戊糖苷、糠氨酸和 CML）的关系，以及它们与年龄敏感的免疫、肌肉和骨功能测量的可能联系，将通过相关分析和遗传分析的结合而显现出来，而这些分析只有在多组件计划的背景下才可能实现。