Folate binding and transport in heart development

叶酸在心脏发育中的结合和运输

• 批准号: 7115377
• 负责人: RICHARD H. FINNELL
• 金额: $ 24.55万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7115377
• 关键词: apoptosis; cell migration; congenital heart disorder; developmental genetics; dietary constituent; dietary supplements; embryo /fetus; folate; folate deficiency; gene environment interaction; gene targeting; genetically modified animals; histogenesis; homocysteine; laboratory mouse; mammalian embryology; mother /embryo /fetus nutrition; neural crest; nutrient interaction; nutrition related tag; transport proteins; vitamin metabolism

Clinical and experimental evidence suggests that periconceptual folate supplementation reduces the risk for contruncal heart defects (CHD). This protective effect afforded by folic acid is unlikely to be the result of ameliorating a simple maternal folate deficiency. The data also argues against a folic acid deficiency inducing CHDs by limiting the availability of nucleic acids or disrupted transmethylation of genes in the developing embryo. It is likely that complex nutrient-gene interactions regulates the sensitivity of developing embryos to the induction of , or protection from, CHDs. The objective of this research program is to test critical hypotheses involving the regulation of intracellular folate and homocysteine concentrations on conotruncal cardiac development. Project 2 will test the hypothesis that cardiac defects may result from a direct effect of folate insufficiency on embryonic cells and will permit a comparison between these direct effects, and the secondary effects of increased homocysteine concentration. We intend to examine on morphological, molecular and physiological/cellular levels, those developmental processes which are compromised by either the absence of sufficient available folate molecules, or by exposure to elevated concentrations of homocysteine. We also intend to identify those processes that benefit from maternal folate supplementation. Specifically, we will examine the interaction between maternal folate intake and sensitive embryonic genotypes utilizing unique transgenic knockout mouse models in which the folate receptor (Folbp1) and/or the reduced folate carrier (RFC) have been inactivated. The impact of maternal folate and vitamin supplementation on the developmental morphology of the conotruncus in the various embryonic genotypes, as well as Folbp1 and RFC protein expression/distribution, neural crest cell migration and apoptosis patterns, and regulation of downstream gene expression will be assessed. The development of these model systems should greatly improve our understanding of comparable events occurring in humans.

临床和实验证据表明，围概念补充叶酸可降低心脏缺陷（CHD）的风险。叶酸提供的这种保护作用不太可能是改善单纯的母体叶酸缺乏症的结果。这些数据还反对叶酸缺乏通过限制核酸的可用性或破坏发育中胚胎中基因的甲基转移来诱导CHD。复杂的营养-基因相互作用可能调节发育中的胚胎对CHD诱导或保护的敏感性。本研究的目的是检验细胞内叶酸和同型半胱氨酸浓度对圆锥动脉干心脏发育的调节作用。项目2将检验叶酸不足对胚胎细胞的直接影响可能导致心脏缺陷的假设，并将比较这些直接影响和同型半胱氨酸浓度升高的继发影响。我们打算在形态学、分子和生理/细胞水平上研究那些由于缺乏足够的叶酸分子或暴露于高浓度的同型半胱氨酸而受到损害的发育过程。我们还打算确定那些受益于母体补充叶酸的过程。具体而言，我们将研究母体叶酸摄入量和敏感的胚胎基因型之间的相互作用，利用独特的转基因敲除小鼠模型，其中叶酸受体（Folbp 1）和/或还原叶酸载体（RFC）已被灭活。将评估母体叶酸和维生素补充对各种胚胎基因型中的圆锥干发育形态学的影响，以及Folbp 1和RFC蛋白表达/分布、神经嵴细胞迁移和凋亡模式以及下游基因表达的调节。这些模型系统的发展应该大大提高我们对人类发生的类似事件的理解。