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）：由于宫内发育迟缓（IUGR）导致的婴儿低出生体重（LBW），定义为足月妊娠时体重<2500 g，仍然是发展中国家的一个关键问题，是发病率和死亡率的主要原因。据估计，发展中国家所有活产婴儿中几乎有30%是低出生体重儿。在成年期，出生体重不足与非传染性疾病，如2型糖尿病、高血压和冠心病之间有很强的联系。来自微量营养素或蛋白质/能量补充剂干预研究的间接证据表明，没有单一的营养素本身对IUGR负责。对人类和实验动物的研究表明，母亲和可能的胎儿中甲硫氨酸和一碳代谢的扰动影响胎儿生长和婴儿代谢的“编程”，并最终导致观察到的表型。我们已经报道了健康妇女和人类新生儿蛋氨酸代谢的特定妊娠相关变化。啮齿类动物在怀孕期间的等热量蛋白限制，导致IUGR，代谢重编程和后代的长期发病率。在人类中，已观察到母亲B12和叶酸状态与其6岁儿童的胰岛素抵抗之间存在显著相关性。 我们假设，边际蛋白质摄入和微量营养素状态的改变，不足以引起“经典”缺乏综合征，将影响母亲和胎儿的一碳代谢和甲基转移，从而改变胎儿的生长。具体目标是纵向记录母体蛋氨酸、同型半胱氨酸代谢，将其与营养素（蛋白质）摄入、叶酸、B12、吡哆醇状态和胰岛素抵抗措施联系起来。将在妊娠早期和晚期使用新型和创新的稳定同位素标记的甲硫氨酸负荷试验来测量甲硫氨酸代谢、转甲基化和转硫作用。这些数据将与通过饮食回忆、血浆B12、甲基丙二酸、吡哆醇和红细胞叶酸水平估计的母亲的宏量和微量营养素状态相关。蛋氨酸代谢的生理测量将使我们能够确定营养状况的亚临床变化对母亲一碳代谢的影响。这些生理数据将与通过出生体重和身体成分评估的胎儿生长以及脐带血中的代谢和激素评估相关。 这些研究将确定IUGR的机制，并导致在确定的关键时期在怀孕期间使用各种甲基供体的战略建议的发展，以防止立即新生儿和长期的“编程”后果的婴儿的目标。当人们考虑到LBW的巨大规模、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意义。