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

描述：NIH独立之路奖的总体目的是为了让霍尔博士获得 需要额外的培训，以发展成为能够进行研究的独立调查员 研究营养和环境因素之间的相互作用。以营养学背景为基础 和流行病学，该奖项的指导阶段将提供1)研究管理和 2)先进的营养生物化学和一碳代谢的数学模型， 3)实验科学。所获得的技能将应用于当前的研究领域，调查 一碳代谢中的营养物质对砷和砷甲基化的影响 基因组DNA。具体地说，胆碱和甜菜碱这两种营养素的作用--即参与 甲基化途径-以前没有考虑过与AS和DNA甲基化有关的途径， 将会被检查。70多个国家和地区的约1.4亿人长期接触AS- 受污染的饮用水浓度远远超过世界卫生组织10%的标准 AS是一种I类致癌物质，可导致皮肤癌、膀胱癌和肺癌以及缺血性癌症。 心脏病和神经损伤。将摄入的无机砷(InAs)甲基化为甲基亚砷酸- (MMA)和二甲基砷酸(DMA)依赖于营养依赖的一碳代谢，促进 尿液排出。DNA通过一碳代谢的甲基化是一种表观遗传修饰， 在调节基因表达和维持染色体稳定性方面发挥关键作用，并可能发挥 在砷致癌的潜在机制中的作用。在指导阶段， 胆碱和甜菜碱对AS和DNA甲基化的影响将在现有的横断面研究中进行 375名孟加拉国成年人暴露在饮用水中各种浓度的砷中。在独立的 在培训阶段，将应用在培训期间获得的技能来进一步研究胆碱和 甜菜碱，包括它们与其他营养物质，即叶酸和肌酸在两者甲基化过程中的相互作用 和DNA利用来自600人的长期随机对照试验的数据和生物样本 暴露在砷中。此外，一碳代谢的数学模型将被用来在 与临床试验相结合的硅胶实验。这些实验将1)允许模型进一步 对照临床试验数据进行验证，以及2)提供对以下结果的更深层次的机制理解 审判。在这个奖项结束时，霍尔博士将发展成为一个独立的多学科 研究人员处于有利地位，可以开发与营养/环境作用相关的其他假说 疾病发展中的相互作用。

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.