FOLIC ACID AND HOMOCYSTEINE: MECHANISMS OF HEART DEFECTS

叶酸和同型半胱氨酸：心脏缺陷的机制

• 批准号: 6941288
• 负责人: THOMAS H. ROSENQUIST
• 金额: $ 123.82万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6941288
• 关键词: congenital heart disorder; embryo /fetus toxicology; folate; homocysteine; nutrient interaction; nutrition related tag

The central theme and overall objective of this program is to determine the biological mechanisms whereby folic acid insufficiency and hyperhomocysteinemia may contribute to abnormal development of the heart. This program project is designed to provide maximum focus upon this theme, and to optimize scientific and intellectual synergy among members of the research team. Discovery of the cellular mechanisms that provide this protection is the objective of the research program proposed here. Two hypotheses will be tested: Hyperhomocysteinemia that results from folic acid insufficiency may induce abnormal development of the conotruncal region of the heart, as well as other neural crest and neural tube derivatives, by inhibiting the function of N-methyl-D-aspartate receptors (NMDA). Folate insufficiency also may induce abnormal development by a direct effect upon the growth and differentiation of neural crest and neural tube cells directly, for example, by limiting the availability of methyl groups for gene methylation. A principle objective of this research program is to sort out the biological effects of low folate from those of hyperhomocysteinemia; and to determine how these two mechanisms may interact. It is inferred that they converge upon processes that are especially critical to the cardiac neural crest, other regions of the neural crest, and the neural tube. Project 1 will examine the teratogenic interaction of homocysteine with other NMDA antagonists, and will determine the degree to which embryos can be rescued by NMDA activation. Project 2 will investigate the impact of impaired folate binding and transport on the development of the heart, as well as other neural crest and neural tube derivatives, using transgenic mouse embryos models made for this purpose. Project 3 will concentrate upon the relative roles of hyperhomocysteinemia and the NMDA on the one hand, and folate insufficiency on the other, as they impact on neural crest cell migration and differentiation. Project 4 will test the elements of each of these hypotheses in a population-based study.

该计划的中心主题和总体目标是确定叶酸缺乏和高同型半胱氨酸血症可能导致心脏异常发育的生物学机制。该计划项目旨在最大限度地关注这一主题，并优化研究团队成员之间的科学和智力协同。发现提供这种保护的细胞机制是这里提出的研究计划的目标。将检验两种假设：叶酸缺乏引起的高同型半胱氨酸血症可能通过抑制N-甲基-D-天冬氨酸受体(NMDA)的功能而导致心脏圆锥干区以及其他神经脊和神经管衍生物的异常发育。叶酸缺乏也可能通过直接影响神经脊和神经管细胞的生长和分化而导致异常发育，例如，通过限制可用于基因甲基化的甲基。这项研究计划的一个主要目标是区分低叶酸和高同型半胱氨酸血症的生物学效应；并确定这两种机制如何相互作用。据推测，它们汇聚在对心脏神经脊、神经脊的其他区域和神经管特别关键的突起上。项目1将研究同型半胱氨酸与其他NMDA拮抗剂的致畸作用，并将确定NMDA激活可以挽救胚胎的程度。项目2将利用为此目的制作的转基因小鼠胚胎模型，调查叶酸结合和运输受损对心脏发育以及其他神经脊和神经管衍生品的影响。项目3将集中于高同型半胱氨酸血症和NMDA，以及叶酸不足的相对作用，因为它们影响神经脊细胞的迁移和分化。项目4将在一项以人口为基础的研究中测试这些假设中的每一个要素。