Maternal One Carbon Metabolism and Low Birth Weight Infant

母亲一碳代谢与低出生体重婴儿

• 批准号: 8512361
• 负责人: SATISH C KALHAN
• 金额: $ 18.6万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8512361
• 关键词: 6 year old; Adult; Affect; Amino Acids; Animals; Asia; Birth Weight; Body Composition; Carbon; Cells; Child; Clinical; Communicable Diseases; Coronary heart disease; Data; Developing Countries; Development; Diabetes Mellitus; Diet; Dietary Proteins; Disease; Economic Burden; Erythrocytes; Essential Amino Acids; Fetal Development; Fetal Growth; Fetal Growth Retardation; Fetus; Field Workers; Folate; Folic Acid; Gene Expression; Genes; Glycine; Goals; Health; Homocysteine; Homocystine; Hormonal; Human; Human Resources; Hypertension; India; Individual; Infant; Infusion Technique; Insulin Resistance; Intervention; Intervention Studies; Intravenous; Label; Lead; Life; Live Birth; Low Birth Weight Infant; Measurement; Measures; Mediator of activation protein; Metabolic; Metabolism; Methionine; Methionine Metabolism Pathway; Methods; Methylmalonic Acid; Micronutrients; Morbidity - disease rate; Mothers; Neonatal; Newborn Infant; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Nutritional; Nutritional status; Obesity; Organ; Phenotype; Physiological; Placenta; Plasma; Population Study; Pregnancy; Proteins; Public Health; Pyridoxine Deficiency; Recommendation; Reporting; Research Infrastructure; Rodent; Role; Sampling; Serine; Societies; Stable Isotope Labeling; Syndrome; Taurine; Testing; Tracer; Umbilical Cord Blood; Vitamins; Weight; Woman; base; cell growth; critical period; economic implication; experience; field study; folic acid metabolism; gene interaction; health economics; hypertensive heart disease; in vivo; innovation; mortality; mother nutrition; neonate; novel; prevent; programs; protein intake; public health relevance; pyridoxine; transmethylation

DESCRIPTION (provided by applicant): Low birth weight (LBW) in infants, due to intrauterine growth retardation (IUGR), defined as weight < 2500gms at term gestation, remains a critical problem in the developing countries and is a major contributor to the morbidity and mortality. It is estimated that almost 30% of all live births in developing countries are LBW. A strong association has been shown in adulthood between LBW and non-communicable diseases, such as type 2 diabetes, hypertension and coronary heart disease. Indirect evidence from intervention studies of micronutrient or protein/energy supplement suggests that no single nutrient is itself responsible for the IUGR. Studies with humans and experimental animals have shown that perturbation in the methionine and one carbon metabolism in the mother and possibly in the fetus, impacts fetal growth and "programming" of the metabolism of the infant and ultimately causes the observed phenotype. We have reported specific gestational-related changes in methionine metabolism in healthy women and in the human newborn infant. Isocaloric protein restriction in rodents during pregnancy, results in IUGR, metabolic re-programming, and long term morbidity in the off spring. In humans, a significant correlation between maternal B12 and folate status and insulin resistance in their children at age 6 years has been observed. We hypothesize that marginal protein intake and altered micronutrient status, insufficient to cause "classical" deficiency syndrome, will impact one carbon metabolism and methyl transfers in the mother and the fetus and thereby alter fetal growth. The specific aims are to longitudinally document maternal methionine, homocysteine metabolism, relate it to nutrient (protein) intake, folate, B12, pyridoxine status, and measures of insulin resistance. Methionine metabolism, transmethylation and transsulfuration, will be measured using a novel and innovative stable isotope labeled methionine loading test early and late in gestation. These data will be related to the macro and micronutrient status of the mother estimated by dietary recall, plasma B12, methylmalonic acid, pyridoxine and red blood cell folate levels. The physiological measurements of methionine metabolism will allow us to identify the effect of subclinical changes in nutrient status on the one carbon metabolism of the mother. These physiological data will be related to fetal growth as assessed by birth weight and body composition, and metabolic and hormonal assessments in the cord blood. These studies will identify the mechanism of IUGR and lead to the development of strategic recommendations at the identified critical periods in pregnancy using various methyl donors with the goal of preventing both immediate neonatal and long term "programming" consequences in the baby. There are major public health and economic implications for this study, when one considers the enormous magnitude of the LBW, the associated clinical problems and the economic burden to the society.

描述（由申请人提供）：婴儿的低出生体重（LBW），由于宫内增长迟滞（IUGR），定义为妊娠期间的体重<2500gms，在发展中国家仍然是一个关键问题，并且是导致发病率和死亡率的主要贡献。据估计，在发展中国家，几乎30％的活生生是LBW。在LBW和非传染性疾病（例如2型糖尿病，高血压和冠状动脉疾病）之间的成年期已经显示出很强的关联。微量营养素或蛋白质/能量补充剂的干预研究的间接证据表明，没有单一营养素本身是IUGR的原因。对人类和实验动物的研究表明，蛋氨酸和胎儿中的一种碳代谢的扰动会影响婴儿的代谢的胎儿生长和“编程”，并最终导致观察到的表型。我们报道了健康女性和人类新生婴儿蛋氨酸代谢的特定特定变化。妊娠期间啮齿动物的等离子蛋白质限制，IUGR导致春季春季的代谢重新编程和长期发病率。在人类中，已经观察到6岁时的儿童孕产妇B12与叶酸状况与胰岛素抵抗之间的显着相关性。 我们假设边缘蛋白的摄入量和微量营养素状态改变，不足以引起“经典”缺乏综合征，将影响母亲和胎儿中的一种碳代谢和甲基转移，从而改变胎儿的生长。具体目的是纵向记录母体蛋氨酸，同型半胱氨酸代谢，将其与养分（蛋白质）摄入，叶酸，B12，吡rid毒素状态以及胰岛素抵抗的测量有关。蛋氨酸代谢，转甲基化和透明硫化将使用一种新型且创新的稳定同位素标记为蛋氨酸载荷试验的早期和后期妊娠中的新型和创新的同位素。这些数据将与饮食召回，血浆B12，甲基丙二酸，吡ido醇和红细胞叶酸水平估计的母亲的宏观和微量营养素状态有关。蛋氨酸代谢的生理测量方法将使我们能够确定营养状况的亚临床变化对母亲一种碳代谢的影响。这些生理数据将与胎儿生长有关，如出生体重和身体成分评估，以及脐带血中的代谢和激素评估。 这些研究将确定IUGR的机制，并通过使用各种甲基供体在怀孕的关键时期发展战略建议，以防止婴儿立即和长期的“编程”后果。当人们认为LBW的巨大幅度，相关的临床问题和社会的经济负担时，这项研究具有重大的公共卫生和经济影响。