Tuning-Up Human Metabolism

职位描述(申请人提供)：K05高级科学家资助金(NCCAM)。艾姆斯出版了450多种出版物，一直跻身各领域被引用最多的几百名科学家之列；荣誉包括国家科学奖章和日本奖。作为先驱/领导者的职业生涯：基因调控；遗传毒理学；诱变；癌症预防；内源性氧化剂/抗氧化剂；营养与健康；线粒体衰变；衰老。加州大学伯克利分校研究生院教授。奥克兰研究所儿童医院的高级科学家，在一栋新装修的大楼里有一个大实验室。科学焦点：一项主要综述的结果显示，大约50种不同的人类遗传病是由于突变酶对辅酶的结合亲和力(Km)较差，可以通过喂食高剂量B维生素来补救，这种B族维生素可以提高相应辅酶的水平；许多多态也会降低酶对辅酶的亲和力。我们建议通过以下方式扩展这一KM概念：1)测试大剂量B维生素对影响辅酶KM酶的KM的多态所引起的表型的有效性，例如MTHFR中同型半胱氨酸的积累：核黄素；一半亚洲人的酒精耐受：烟酸。2)测试其他代谢物和微量营养素的有效性。3)确定线粒体氧化衰退是否会导致酶与其辅酶失去亲和力，以及是否可以通过喂食高剂量的B维生素来改善这一点。先前的研究结果表明，高剂量的关键线粒体代谢物可以延缓线粒体的衰变，并牵涉到KM。4)通过优化微量营养素水平，最大限度地减少DNA损伤和癌症，特别是在老年人中。

DESCRIPTION (provided by applicant): K05 Senior Scientist Grant (NCCAM). Ames has published more than 450 publications and consistently ranks among the top few hundred of the most-cited-scientists in all fields; honors include The National Medal of Science & The Japan Prize. Career as pioneer/leader in: gene-regulation; genetic toxicology; mutagenesis; cancer prevention; endogenous oxidants/antioxidants; nutrition and health; mitochondrial decay; and aging. Professor of the Graduate School at U.C. Berkeley. Senior Scientist, Children's Hospital of Oakland Research Institute, with large lab in a newly renovated building. Scientific focus: ramifications of a major review showing that about 50 different human genetic diseases due to a poorer binding affinity (Km) of the mutant enzyme for the coenzyme, can be remedied by feeding high dose B vitamins which raise levels of the corresponding coenzyme; many polymorphisms also have lowered affinity of enzyme for coenzyme. We propose to expand this Km concept by: 1) Testing the effectiveness of high dose B vitamins on phenotypes caused by polymorphisms that affect the Km of enzymes for coenzyme, e.g. homocysteine accumulation in MTHFR: riboflavin; alcohol intolerance in half of Asians: niacin. 2) Testing the effectiveness of other metabolites and micronutrients.3) Determining if mitochondrial oxidative decay with age causes enzymes to lose affinity for their coenzymes and if this can be ameliorated by feeding high doses of B vitamins. Previous results showed that high doses of key mitochondrial metabolites delay mitochondrial decay and involve Km. 4) Minimizing DNA damage and cancer by optimizing micronutrient levels, particularly in the elderly.