Interrelationships among nutrients involved in one-carbon metabolism in Banglades

孟加拉国参与一碳代谢的营养素之间的相互关系

• 批准号: 7872084
• 负责人: Megan Nina Hall
• 金额: $ 9.15万
• 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 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7872084
• 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; 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; indium arsenide; mathematical model; methyl group; multidisciplinary; nutrition; oxidation; public health relevance; randomized placebo controlled trial; research study; skills; urinary

DESCRIPTION (provided by applicant) 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 5g/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. Public Health Relevance: On a global basis, WHO estimates that more than 140 million people in at least 70 countries are exposed to arsenic (As)-contaminated drinking water, most in the developing world where nutritional deficiencies are common. The proposed studies of choline and betaine build considerably upon the goals of the research of the parent studies, which is to identify interventions to reduce blood As concentrations (i.e. internal As exposure) through simple, low-cost, low-risk nutritional manipulations of one- carbon metabolism. Previous work by our group has shown that folic acid supplementation in folate-deficient As-exposed individuals facilitated As elimination and significantly lowered blood As concentrations. However, the finding that there were also many individuals who did not appear to be responsive to folic acid suggests the possibility that there is room to improve on the efficacy of FA and that some individuals could potentially benefit from another therapeutic modality such as choline or betaine. Considering the magnitude of the exposed population worldwide, and the severity of the numerous associated health outcomes, the investigators feel this work is highly significant as it implies that simple, low-cost, low-risk interventions could have therapeutic potential for ameliorating the long-term health consequences for the many populations at risk.

描述（由申请人提供） 该NIH独立之路奖的总体目的是让Hall博士获得发展成为能够进行研究以调查营养和环境因素之间相互作用的独立研究员所需的额外培训。 在营养和流行病学背景的基础上，该奖项的指导阶段将提供1）研究管理和监督，2）高级营养生物化学和一碳代谢的数学建模，以及3）实验室科学的培训。所获得的技能将被应用到当前的研究领域，调查参与一碳代谢的营养物质对砷（As）和基因组DNA甲基化的影响。具体而言，两种营养素，胆碱和甜菜碱，即参与甲基化途径的关键营养素的作用，这在以前没有被认为与作为和DNA甲基化，将被检查。全球70多个国家约有1.4亿人长期暴露于砷污染的饮用水中，其浓度远远超过世界卫生组织规定的10.5g/L的标准。 砷是一种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系统损伤。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，并促进尿砷消除。DNA甲基化是一种表观遗传学修饰，在调控基因表达和维持染色体稳定性方面起着重要作用，并可能在砷致癌的潜在机制中发挥作用。在指导阶段，胆碱和甜菜碱对甲基化的影响，作为和DNA将在现有的横断面研究375孟加拉国成年人暴露于广泛的饮用水中的As浓度。在独立阶段，在培训过程中获得的技能将被应用于进一步调查胆碱和甜菜碱的作用，包括它们与其他营养物质，即叶酸和肌酸的相互作用，在甲基化的作为和DNA利用数据和生物标本从一个随机对照试验的600个人长期暴露于作为。此外，将采用一碳代谢的数学模型结合临床试验进行计算机模拟实验。这些实验将1）允许根据临床试验数据进一步验证模型，2）提供对试验结果的更深入的机制理解。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者，能够很好地开发与营养/环境相互作用在疾病发展中的作用有关的其他假设。 公共卫生相关性：在全球范围内，世卫组织估计，至少有70个国家的1.4亿多人暴露于受砷污染的饮用水，其中大多数人在营养不良现象普遍的发展中国家。胆碱和甜菜碱的拟议研究在很大程度上建立在母研究的研究目标基础上，即通过简单、低成本、低风险的一碳代谢营养操作，确定降低血液砷浓度（即体内砷暴露）的干预措施。我们小组以前的工作表明，叶酸缺乏的砷暴露的个人补充叶酸促进作为消除和显着降低血液中的砷浓度。然而，也有许多人似乎对叶酸没有反应的发现表明，FA的疗效有改善的空间，一些人可能从另一种治疗方式（如胆碱或甜菜碱）中受益。考虑到全球暴露人群的规模以及众多相关健康后果的严重性，研究人员认为这项工作非常重要，因为它意味着简单，低成本，低风险的干预措施可能具有改善长期健康后果的治疗潜力。