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: 6783314
• 负责人: THOMAS H. ROSENQUIST
• 金额: $ 120.47万
• 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 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6783314
• 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不足和高同型半胱氨酸血症可能导致心脏发育异常的生物学机制。该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作用。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。将检验两个假设： 高同型半胱氨酸血症是由叶酸不足引起的 可能会导致锥体干区的异常发育， 心脏，以及其它神经嵴和神经管衍生物， 通过抑制N-甲基-D-天冬氨酸受体的功能 （NMDA）。 叶酸不足也可能通过以下途径诱导发育异常： 直接影响神经嵴的生长和分化 和神经管细胞直接，例如，通过限制 基因甲基化的甲基可用性。这项研究计划的主要目标是从高同型半胱氨酸血症中找出低叶酸的生物学效应，并确定这两种机制如何相互作用。据推断，它们会聚在对心脏神经嵴、神经嵴的其他区域和神经管特别重要的过程上。项目1将研究高半胱氨酸与其他NMDA拮抗剂的致畸相互作用，并确定胚胎可以通过NMDA激活而获救的程度。项目2将研究叶酸结合和转运受损对心脏发育的影响，以及其他神经嵴和神经管衍生物，使用为此目的制作的转基因小鼠胚胎模型。项目3将集中在高同型半胱氨酸血症和NMDA的相对作用，一方面，叶酸不足的另一方面，因为它们对神经嵴细胞迁移和分化的影响。项目4将在一项以人口为基础的研究中检验这些假设中每一项的要素。