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: 6527717
• 负责人: THOMAS H. ROSENQUIST
• 金额: $ 102.13万
• 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/6527717
• 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.

该项目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异常发育的生物学机制。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。两种假设将被验证：叶酸不足导致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，诱导心脏锥体区以及其他神经嵴和神经管衍生物的异常发育。叶酸不足还可能通过直接影响神经嵴和神经管细胞的生长和分化，例如，通过限制基因甲基化甲基的可用性，诱导异常发育。这项研究计划的一个主要目标是将低叶酸与高同型半胱氨酸血症的生物学效应区分开来；并确定这两种机制是如何相互作用的。据推测，它们聚集在对心脏神经嵴、神经嵴的其他区域和神经管特别关键的过程上。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NMDA激活可以挽救胚胎的程度。项目2将使用转基因小鼠胚胎模型，研究受损的叶酸结合和运输对心脏以及其他神经嵴和神经管衍生物发育的影响。项目3将集中于高同型半胱氨酸血症和NMDA的相对作用，以及叶酸不足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的要素。