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: 8133499
• 负责人: Megan Nina Hall
• 金额: $ 4.66万
• 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/8133499
• 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; 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） 这项NIH独立奖的总体目的是霍尔博士获得进一步的培训，以开发成能够进行研究以研究营养和环境因素之间相互作用的独立研究人员。 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）研究和监督的培训，2）先进的营养生物化学和一碳代谢的数学建模，以及3）实验室科学。获得的技能将应用于目前的研究领域，研究一碳代谢对砷（AS）和基因组DNA甲基化的养分的影响。具体而言，将研究两种营养素，即胆碱和甜菜碱的作用，即与AS和DNA甲基化有关的甲基化途径所涉及的关键营养素。在70多个国家/地区，大约有1.4亿人的浓度远远超过了世界卫生组织标准的10 5G/L。 正如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）甲基化至甲基苯酚（MMA）和二甲基氨基甲酸（DMA）依赖于营养依赖性的一种碳代谢，并促进尿液作为消除。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起着关键作用，并且可能在AS诱导的癌变的潜在机制中起作用。在指导阶段，将在现有的375名孟加拉国成年人的横截面研究中研究胆碱和甜菜碱对AS和DNA的甲基化的影响，暴露于饮用水中的广泛浓度。在独立阶段，将采用训练期间获得的技能，以进一步研究胆碱和甜菜碱的作用，包括它们与其他营养物质的相互作用，即叶酸和肌酸，在AS的甲基化中使用数据和DNA的甲基化，并从600个摄影的随机对照试验中使用了数据和生物测量。此外，将采用一碳代谢的数学模型与临床试验一起进行硅实验。这些实验将1）允许模型与临床试验数据进一步验证，2）对试验结果提供了更深入的机械理解。在该奖项结束时，霍尔博士将发展成为一个独立的多学科研究者，旨在发展与营养/环境相互作用在疾病发展中的作用相关的其他假设。 公共卫生相关性：在全球范围内，他估计至少有70个国家 /地区有超过1.4亿人接触到砷（AS）受污染的饮用水，大多数在营养缺乏症的发展中国家中，大多数人很常见。提出的对胆碱和甜菜碱的研究基于父母研究的目标的基础，这是为了通过一种简单的，低成本的低风险，低风险的营养操纵来确定降低血液作为浓度（即内部接触）的干预措施。我们小组的先前工作表明，叶酸缺陷的叶酸含量促进了消除，并显着降低了血液作为浓度。但是，发现也有许多人似乎对叶酸有反应的发现表明，有可能提高FA功效的空间，并且有些人可能会从其他治疗方式中受益，例如胆碱或菜碱。考虑到全世界暴露的人口的大小以及众多相关的健康结果的严重性，研究人员认为这项工作非常重要，因为它暗示着简单，低成本，低风险的干预措施可能会对许多人群减轻长期健康后果具有治疗潜力。