Nutrients involved 1-carbon metabolism and the methylation of arsenic and DNA

涉及 1-碳代谢以及砷和 DNA 甲基化的营养素

• 批准号: 8467716
• 负责人: Megan Nina Hall
• 金额: $ 24.4万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8467716
• 关键词: Accounting; Adult; Anabolism; Area; Arsenic; Award; Bangladesh; Betaine; Biological; Bladder; Blood; Cacodylic Acid; Cancer Etiology; Carbon; Carcinogens; Choline; Chromosomal Stability; Clinical Trials; Computer Simulation; Country; Creatine; Creatinine; Cross-Sectional Studies; DNA; DNA Methylation; Data; Development; Diet; Disease; Endogenous Retroviruses; Environment; Environmental Risk Factor; Epidemiology; Epigenetic Process; Excretory function; Folate; Folic Acid; Folic Acid Deficiency; Funding; Gene Expression Regulation; Genomics; Goals; Health; Hepatic; High Prevalence; Homocysteine; Homocystine; Human; Hyperhomocysteinemia; Impairment; Individual; Intervention; Laboratories; Leukocytes; Lung; Maintenance; Malnutrition; Measurement; Mentors; Metabolism; Methionine; Methylation; Methyltransferase; Modality; Modeling; Modification; Myocardial Ischemia; Neurologic; Nutrient; Nutritional; Nutritional Biochemistry; Outcome; Parents; Participant; Pathway interactions; Phase; Plasma; Play; Population; Populations at Risk; Positioning Attribute; Process; Production; Randomized Controlled Trials; Reaction; Research; Research Personnel; Risk; Role; S-Adenosylmethionine; Sampling; Science; Severities; Skin Cancer; Supplementation; System; Testing; Therapeutic; Time; Training; United States National Institutes of Health; Universities; Vitamin B Complex; Work; World Health Organization; arm; base; betaine-homocysteine methyltransferase; carcinogenesis; cost; design; drinking water; improved; mathematical model; methyl group; multidisciplinary; nutrition; oxidation; randomized placebo controlled trial; research study; skills; urinary

DESCRIPTION: The overall purpose of this NIH Pathway to Independence Award is for Dr. Hall to gain the additional training needed to develop into an independent investigator capable of conducting studies to investigate interactions between nutritional and environmental factors. Building upon a background in nutrition and epidemiology, the mentored phase of this award will provide training in 1) study management and oversight, 2) advanced nutritional biochemistry and the mathematical modeling of one-carbon metabolism, and 3) laboratory sciences. The acquired skills will be applied to the current area of research, investigating the influence of nutrients involved in one-carbon metabolism on the methylation of both arsenic (As) and genomic DNA. Specifically, the roles of two nutrients, choline and betaine - i.e. key nutrients involved in methylation pathways - which have not previously been considered in relation to As and DNA methylation, will be examined. Roughly 140 million people in over 70 countries are chronically exposed to As- contaminated drinking water at concentrations far exceeding the World Health Organization standard of 10 ¿g/L. As is a class I carcinogen known to cause cancers of the skin, bladder, and lung, as well as ischemic heart disease and neurologic impairments. Methylation of ingested inorganic arsenic (InAs) to methylarsonic- (MMA) and dimethylarsinic acids (DMA) relies on nutrient-dependent one carbon metabolism and facilitates urinary As elimination. Methylation of DNA via one-carbon metabolism is an epigenetic modification that plays critical roles in the regulation of gene expression and maintenance of chromosomal stability, and may play a role in the underlying mechanism of As-induced carcinogenesis. In the mentored phase, the influence of choline and betaine on methylation of As and DNA will be investigated in an existing cross-sectional study of 375 Bangladeshi adults exposed to a wide range of As concentrations in drinking water. In the independent phase, the skills acquired during the training will be applied to further investigate the roles of choline and betaine, including their interactions with other nutrients, i.e. folate and creatine, in the methylation of both As and DNA utilizing data and biospecimens from a randomized controlled trial of 600 individuals chronically exposed to As. In addition, mathematical models of one-carbon metabolism will be employed to conduct in silico experiments in conjunction with the clinical trial. These experiments will 1) allow the models to be further validated against the clinical trial data and 2) provide a deeper mechanistic understanding of the results from the trial. At the conclusion of this award, Dr. Hall will have developed into an independent multidisciplinary investigator well positioned to develop additional hypotheses related to the role of nutrient/environment interactions in disease development.

描述：这项NIH独立奖的总体目的是霍尔博士获得 需要进行其他培训才能发展为独立研究者，能够进行研究 研究营养和环境因素之间的相互作用。基于营养背景 和流行病学，该奖项的修订阶段将在1）研究管理和 监督，2）先进的营养生物化学和一碳代谢的数学建模， 3）实验室科学。获得的技能将应用于目前的研究领域，调查 一碳代谢涉及的养分对砷（AS）和 基因组DNA。具体而言，胆碱和甜菜碱的两种营养素的作用 - 即关键营养素 甲基化途径 - 以前尚未考虑与AS和DNA甲基化有关 将被检查。长期以来，超过70个国家 /地区的大约1.4亿人暴露于 浓度远远超过世界卫生组织标准10的饮用水 »g/l。与I类致癌物一样，会引起皮肤，膀胱和肺的癌症，以及缺血性 心脏病和神经系统障碍。摄入的无机砷（INAS）甲基化至甲基虫 （MMA）和二甲基苯胺酸（DMA）依赖于营养依赖性的一种碳代谢，并促进 尿作为消除。通过单碳代谢的DNA甲基化是一种表观遗传修饰， 在调节基因表达和染色体稳定性的维持中的关键作用，并可能发挥作用 在AS诱导的癌变的基本机制中的作用。在修改阶段， 在现有 375名孟加拉国成年人暴露于饮用水中的广泛浓度。在独立 阶段，将采用培训期间获得的技能，以进一步研究胆碱和 甜菜碱，包括它们与其他营养素的相互作用，即叶酸和创造，在两者的甲基化中 和DNA利用600个个体的随机对照试验的数据和生物测量长期长期 暴露于AS。此外，将进行一碳代谢的数学模型以进行 硅实验与临床试验结合使用。这些实验将1）允许模型进一步 针对临床试验数据进行了验证，2）对 试验。在该奖项结束时，霍尔博士将发展成为独立的多学科 研究人员良好的位置，以开发与营养/环境作用有关的其他假设 疾病发展中的相互作用。