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: 7078049
• 负责人: THOMAS H. ROSENQUIST
• 金额: $ 1.06万
• 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/7078049
• 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异常发育的生物学机制。该计划项目旨在最大程度地关注这一主题，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本文提出的研究计划的目标。将测试两个假设：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，诱导心脏圆锥干区域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来诱导发育异常，例如通过限制基因甲基化的甲基的可用性。该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效应；并确定这两种机制如何相互作用。据推测，它们集中在对心脏神经嵴、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 将使用为此目的制作的转基因小鼠胚胎模型，研究叶酸结合和运输受损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 将一方面关注高同型半胱氨酸血症和 NMDA 的相对作用，另一方面关注叶酸不足的相对作用，因为它们影响神经嵴细胞迁移和分化。项目 4 将在基于人群的研究中测试每个假设的要素。

项目成果

Risks of selected congenital malformations among offspring of mixed race-ethnicity.

混合种族后代中特定先天畸形的风险。

• DOI: 10.1002/bdra.20054
• 发表时间: 2004
• 期刊: Birth defects research. Part A, Clinical and molecular teratology
• 作者: Yang,Juan;Carmichael,SuzanL;Kaidarova,Zhanna;Shaw,GaryM
• 通讯作者: Shaw,GaryM

Nutrient effects upon embryogenesis: folate, vitamin A and iodine.

对胚胎发生影响的营养物质：叶酸、维生素 A 和碘。

• DOI: 10.1159/000082592
• 发表时间: 2005
• 期刊: Nestle Nutrition workshop series. Paediatric programme
• 作者: Rosenquist,ThomasH;vanWaes,JaneeGelineau;Shaw,GaryM;Finnell,Richard
• 通讯作者: Finnell,Richard

Another key role for the cardiac neural crest in heart development.

心脏神经嵴在心脏发育中的另一个关键作用。

• DOI: 10.1152/ajpheart.01218.2006
• 发表时间: 2007
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: Rosenquist,ThomasH;Finnell,RichardH
• 通讯作者: Finnell,RichardH

The expression of the NR1-subunit of the NMDA receptor during mouse and early chicken development.

NMDA 受体 NR1 亚基在小鼠和早期鸡发育过程中的表达。

• DOI: 10.1016/j.reprotox.2006.03.010
• 发表时间: 2006
• 期刊: Reproductive toxicology (Elmsford, N.Y.)
• 作者: Bennett,GregoryD;Moser,Kristine;Chaudoin,Tammy;Rosenquist,ThomasH
• 通讯作者: Rosenquist,ThomasH

Microarray analysis of homocysteine-responsive genes in cardiac neural crest cells in vitro.

体外心脏神经嵴细胞同型半胱氨酸反应基因的微阵列分析。

• DOI: 10.1002/dvdy.21101
• 发表时间: 2007
• 期刊: Developmental dynamics : an official publication of the American Association of Anatomists
• 作者: Rosenquist,TH;Bennett,GD;Brauer,PR;Stewart,ML;Chaudoin,TR;Finnell,RH
• 通讯作者: Finnell,RH