COLLAGEN BIOCHEMISTRY

项目5将在600只UM-HET3基因分型雌性小鼠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。该测试电池还将在种群2中的180只小鼠身上进行，以查看被选为等位基因延长寿命的小鼠是否也表现出蛋白质糖基化和氧化水平的降低。这套测试包括测量胶原糖基化(呋喃)和糖氧化产物戊糖苷和N/epsilon-羧甲基-赖氨酸，从以前的工作中知道，它们随年龄增长的速度在不同的近交系中有所不同，并且对卡路里限制的年龄延缓效应很敏感。来自项目5的数据将证实和扩展试点工作，表明UM-HET3小鼠种群中的蛋白质糖基化和糖氧化受到基因控制，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的热稳定性，尾腱胶原是胶原蛋白交联的敏感标志。这些加合物与代谢状态的其他标记物(戊糖苷、呋喃和慢性粒细胞白血病)的关系，以及它们与年龄敏感的免疫、肌肉和骨骼功能测量的可能联系，将从相关分析和遗传分析的组合中浮现出来，只有在多组分计划的背景下才有可能。

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.