Tuning-Up Human Metabolism

描述（由申请人提供）：K05高级科学家资助（NCCAM）。艾姆斯发表了450多篇论文，在所有领域被引用次数最多的前几百名科学家中一直名列前茅；荣誉包括国家科学奖章和日本奖。在基因调控领域的先驱/领导者；遗传毒理学;诱变;癌症预防;内源性氧化剂/抗氧化剂;营养和健康；线粒体衰变;和老化。加州大学伯克利分校研究生院教授。奥克兰儿童医院研究所的资深科学家，在新装修的建筑中拥有大型实验室。科学焦点：一项重大审查的结果表明，由于突变酶对辅酶的结合亲和力（Km）较差，大约50种不同的人类遗传疾病可以通过喂食高剂量的B族维生素来纠正，从而提高相应辅酶的水平；许多多态性也降低了酶对辅酶的亲和力。我们建议通过以下方式扩展Km概念：1)测试高剂量B族维生素对影响辅酶Km的多态性引起的表型的有效性，例如MTHFR中的同型半胱氨酸积累：核黄素；半数亚洲人酒精不耐受：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随着年龄的增长而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族维生素来改善这种情况。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衰变并涉及Km。4)通过优化微量营养素水平来减少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.