Stable isotope evaluation of the methionine cycle in undernourished pregnancy

营养不良妊娠中蛋氨酸循环的稳定同位素评估

• 批准号: 8986457
• 负责人: PETER W. NATHANIELSZ
• 金额: $ 3.28万
• 依托单位: UNIVERSITY OF WYOMING
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8986457
• 关键词: Stable; isotope; evaluation; methionine; cycle

DESCRIPTION (provided by applicant): The methionine (MET) cycle is central to methylation in developmental processes (e.g. gene-environment interactions). Impaired methyl transfers have structural and metabolic consequences e.g. neural tube defects and high homocysteine (HCYS). Gene methylation is a fundamental mechanism leading to persistent epigenetic changes. Maternal under-nutrition and IUGR results in epigenetic changes in fetal tissues, including decreased methylation that increases gene expression. We have developed a baboon non-human primate (NHP) model of moderate maternal nutrient restriction (MNR) resulting in IUGR. MNR mothers eat 70% of controls (CTR) eating ad lib. In MNR, fetal vitamin B12 is decreased 22% while folate is unchanged. Rat studies show hyperhomocysteinemia is associated with increases in both plasma HCYS inflow and outflow. However NHP data are needed since rat 1-CC function differs from primates. Central to our proposal to develop these techniques in an IUGR NHP model, rat studies in pregnancy show that plasma fluxes under- estimate by >80% absolute tissue HCYS production e.g. little maternal or fetal hepatic HCYS is exported to plasma. Thus, plasma HCYS does not reflect major MET cycle tissue activity. As a consequence, MET cycle dysfunction does not necessarily lead to elevated HCYS and can occur with normal plasma HCYS. B12 is essential for methyl group transfer from 5-methyl-tetrahydrofolate to methylate HCYS to MET. HYPOTHESIS: MNR decreases B12 availability to the fetal MET cycle decreasing 1) overall HCYS methylation 2) contribution of HCYS methylation in maternal and fetal tissues to plasma HCYS. APPROACH: In stable isotope studies at 0.9 gestation in pregnant baboons chronically instrumented with maternal and fetal catheters maintained on a tether system, we use a priming dose followed by constant infusion of the tracers [U-13C] MET and [1-13C] HCYS to determine HCYS methylation and HCYS kinetics in both CTR and MNR pregnancies. Our collaborators methods in pregnant rats are now in Press. INNOVATION: Human studies cannot 1) control and match pre-study maternal phenotype, 2) precisely control nutrient intake; 3) obtain maternal and fetal tissues. Novelty lies in combining a unique NHP model and a pressing developmental question. R03 RESPONSIVENESS: The R03 mechanism encourages novel, high-risk studies. These isotope techniques have never been performed in any precocial species. INVESTIGATORS have many years experience with perinatal baboon studies and have published extensively on this NHP MNR/IUGR fetal phenotype. ENVIRONMENT: Our baboon feeding facility is unique worldwide to produce controlled MNR and IUGR. RELEVANCE: Primate and rodent MET cycle metabolism differs markedly. Identification of alterations in tissue methylation will provide evidence of tissues in which MET cycle dysfunction occurs with resultant epigenetic changes. Information will translate to human pregnancy aiding diagnostic, preventative and therapeutic strategies. B12 has been ignored in comparison to folic acid.

描述（由申请人提供）：蛋氨酸（MET）周期在发育过程中甲基化（例如基因 - 环境相互作用）至关重要。甲基转移受损具有结构和代谢后果，例如神经管缺陷和高同型半胱氨酸（HCY）。基因甲基化是导致持续表观遗传变化的基本机制。母体不足和IUGR导致胎儿组织的表观遗传变化，包括减少甲基化，增加基因表达。我们已经开发了一种中度母体营养限制（MNR）的狒狒非人类灵长类动物（NHP）模型，导致IUGR。 MNR母亲吃70％的对照（CTR）吃Ad Lib。在MNR中，叶酸不变，胎儿维生素B12降低了22％。大鼠研究表明，高脑类结晶血症与血浆HCYS流入和流出的增加有关。但是，需要NHP数据，因为大鼠1CC函数与灵长类动物的不同。我们在IUGR NHP模型中开发这些技术的提议的核心，妊娠中的大鼠研究表明，血浆滤器估计低于80％的绝对组织HCYS生产，例如几乎没有母体或胎儿肝HCY出口到等离子体。因此，血浆HCY不反映主要的MET循环组织活性。结果，MET循环功能障碍并不一定会导致HCY升高，并且可能发生正常的血浆HCY。 B12对于从5-甲基四氢叶酸到甲基化HCY的甲基转移至关重要。假设：MNR降低B12对胎儿MET周期的可用性减少1）总体HCYS甲基化2）母体和胎儿组织中HCYS甲基化对血浆HCY的贡献。方法：在稳定的同位素研究中，妊娠0.9妊娠狒狒的妊娠狒狒，长期用母体和胎儿导管保持在系绳系统上，我们使用启动剂量，然后不断输注示踪剂[u-13c] met和[1-13c] hcys [1-13c] hcys确定CTR和MNR妊娠中的HCYS甲基化和HCYS动力学。我们在怀孕大鼠中的合作者方法现在正在印刷中。创新：人类研究不能1）控制和匹配研究前的母体表型，2）精确控制营养摄入； 3）获得母体和胎儿组织。新颖的谎言 在结合独特的NHP模型和紧迫的发展问题时。 R03响应能力：R03机制鼓励新的高风险研究。这些同位素技术从未在任何早熟物种中进行。研究人员有多年的围产期狒狒研究经验，并广泛发表了有关这种NHP MNR/IUGR胎儿表型的经验。环境：我们的狒狒喂食设施在全球范围内独特，可以生产受控的MNR和IUGR。相关性：灵长类动物和啮齿动物的代谢遇到了明显不同。鉴定组织甲基化的改变将提供组织的证据，其中MET循环功能障碍随着导致的表观遗传变化而发生。信息将转化为人类怀孕的诊断，预防和治疗策略。与叶酸相比，B12被忽略了。