Tuning-Up Human Metabolism

描述（由申请人提供）：K 05高级科学家资助（NCCAM）。艾姆斯发表了450多篇出版物，并一直在所有领域被引用最多的科学家中排名前几百位;荣誉包括国家科学奖章和日本奖。作为先锋/领导者的职业生涯：基因调控;遗传毒理学;突变;癌症预防;内源性氧化剂/抗氧化剂;营养和健康;线粒体衰退;和衰老。加州大学研究生院教授伯克利 奥克兰研究所儿童医院高级科学家，在新装修的大楼内设有大型实验室。 科学重点：一项主要综述的结果表明，由于突变酶对辅酶的结合亲和力（Km）较差，约50种不同的人类遗传疾病可以通过喂食高剂量的B族维生素来治疗，这会提高相应辅酶的水平;许多多态性还具有降低的酶对辅酶的亲和力。 我们建议通过以下方式扩展该Km概念：1）测试高剂量B族维生素对由影响辅酶酶Km的多态性引起的表型的有效性，例如MTHFR中的高半胱氨酸积累：核黄素;一半亚洲人的酒精不耐受：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会随着年龄的增长导致酶失去对其辅酶的亲和力，以及是否可以通过喂食高剂量的B族维生素来改善。先前的结果表明，高剂量的关键线粒体代谢物延迟线粒体衰变，并涉及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.