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: 6899588
• 负责人: THOMAS H. ROSENQUIST
• 金额: $ 0.69万
• 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/6899588
• 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整体目标是确定叶酸不足和高脑结构血症的生物学机制可能导致心脏异常发育。该计划项目旨在最大程度地关注该主题，并优化研究团队成员之间的科学和知识协同作用。发现提供此保护的细胞机制是此处提出的研究计划的目的。将测试两个假设：叶酸不足引起的高质膜结构血症可能会抑制N-甲基-D-天冬氨酸受体（NMDA）的功能，从而诱导心脏的共骨区域以及其他神经rest和神经管衍生物的异常发育。 叶酸功能不全也可能通过直接影响神经rest和神经管细胞的生长和分化的直接影响，例如直接限制甲基甲基化的甲基化甲基化，从而引起异常发育。该研究计划的一个主要目的是列出低叶酸叶酸的生物学作用。并确定这两种机制如何相互作用。可以推断他们会融合对心脏神经rest，神经rest的其他区域以及神经管特别重要的过程。项目1将检查同型半胱氨酸与其他NMDA拮抗剂的致畸相互作用，并将确定可以通过NMDA激活来挽救胚胎的程度。项目2将使用为此目的制定的转基因小鼠胚胎模型研究叶酸结合和转运对心脏发展以及其他神经rest和神经管衍生物的影响。项目3将一方面集中于高脑结膜血症和NMDA的相对作用，另一方面叶酸不足，因为它们会影响神经rest细胞的迁移和分化。项目4将在基于人群的研究中测试这些假设的要素。