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

描述：这个NIH独立之路奖的总体目的是让霍尔博士获得 需要额外的培训，以发展成为能够进行研究的独立研究者， 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以下方面的培训：1）研究管理， 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。所获得的技能将应用于当前的研究领域，调查 研究了参与一碳代谢的营养物质对砷（As）和 基因组DNA具体来说，两种营养素，胆碱和甜菜碱的作用-即参与 甲基化途径-以前没有考虑过与As和DNA甲基化有关， 将被审查。70多个国家的大约1.4亿人长期暴露于As- 受污染的饮用水浓度远远超过世界卫生组织的标准10 微克/升作为一种I类致癌物质，已知会导致皮肤癌、膀胱癌和肺癌，以及缺血性 心脏病和神经损伤。摄入的无机砷（InAs）甲基化为甲基胂酸- (MMA)和二甲基胂酸（DMA）依赖于营养素依赖的一碳代谢， 尿砷消除通过一碳代谢的DNA甲基化是一种表观遗传修饰， 在调节基因表达和维持染色体稳定性方面起着关键作用，并可能发挥重要作用。 在砷诱导的致癌作用的潜在机制的作用。在辅导阶段， 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研究， 375名孟加拉国成年人暴露于饮用水中广泛的As浓度。在独立 阶段，在培训期间获得的技能将被应用于进一步研究胆碱和 甜菜碱，包括它们与其他营养素的相互作用，即叶酸和肌酸，在两个作为甲基化 和DNA利用数据和生物标本从一个随机对照试验的600个人长期 暴露于As。此外，还将采用一碳代谢的数学模型， 计算机实验与临床试验相结合。这些实验将1）允许模型进一步 根据临床试验数据进行验证，2）提供对结果的更深入的机制理解， 庭审在这个奖项结束时，霍尔博士将发展成为一个独立的多学科 研究人员能够很好地开发与营养/环境作用相关的其他假设 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.