Interaction of teratogens in heart development

致畸剂在心脏发育中的相互作用

• 批准号: 6611202
• 负责人: THOMAS H. ROSENQUIST
• 金额: $ 20.43万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6611202
• 关键词: NMDA receptors; chick embryo; congenital heart disorder; embryo /fetus; embryo /fetus toxicology; embryogenesis; folate; genetically modified animals; histogenesis; homocysteine; inhibitor /antagonist; laboratory mouse; mother /embryo /fetus nutrition; nutrient interaction; nutrition related tag; teratogens; toxicant interaction; vertebrate embryology

The biological basis for well-known relationships among conotruncal and neural tube defects is now generally assumed to be found in the common origin of their primordial cells. However, there is no consensus about the mechanism that leads to these defects. A high level of protection of protection is offered for conotruncal, other neural crest, and neural tube defects by folic acid supplementation, implying that an unnamed process of extraordinary importance is sensitively dependent upon an adequate supply of folic acid. For the present proposal, we will test the hypothesis that homocysteine is a teratogen for the conotruncus and other derivatives of the neuroepithelium; and that folic acid supplementation provides protection for embryos by reducing the concentration of homocysteine can induce abnormal development of the conotruncus and other neural crest/neural tube derivatives by acting as an NMDA receptor (NMDA) antagonist. By this mechanism, homocysteine may interact with other NMDA antagonists to exacerbate the teratogenic effect; conversely, it may be predicted that activation of the NMDA would rescue embryos exposed to homocysteine and related compounds. The following specific aims will test this hypothesis. Aim 1, to determine how exogenous NMDA antagonists may interact with homocysteine to exacerbate the disruption of normal development. Aim 2, to measure the degree to which activation of the NMDA may rescue embryos that are treated with homocysteine and related compounds. Aim 3, to analyze changes in gene expression in embryos treated with homocysteine and other NMDA antagonists. SIGNIFICANCE. This proposal offers the first unifying hypothesis regarding a mechanism for a large set of risk factors for abnormal development whose common effect is to inhibit the function of the NMDA. These may include therapeutic drugs, recreation drugs, environmental pollutants, and sequelae of malnutrition. A common mechanism of action would permit these factors to interact in previously unsuspected ways, potentially to exacerbate their respective effects. Effective and comprehensive prevention strategies may be achieved through understanding of such interactive mechanisms.

圆锥锥体缺陷和神经管缺陷之间众所周知的关系的生物学基础，现在普遍认为是在它们的原始细胞的共同起源中发现的。然而，对于导致这些缺陷的机制还没有达成共识。叶酸的补充对圆锥锥体、其他神经嵴和神经管缺陷提供了高水平的保护，这意味着一个非常重要的未命名过程敏感地依赖于充足的叶酸供应。对于目前的提议，我们将测试的假设，即同型半胱氨酸是一种致畸剂的圆锥干和其他衍生的神经上皮；补充叶酸通过降低同型半胱氨酸浓度对胚胎有保护作用，可作为NMDA受体（NMDA）拮抗剂诱导锥体和其他神经嵴/神经管衍生物的异常发育。通过这种机制，同型半胱氨酸可能与其他NMDA拮抗剂相互作用，加剧致畸作用；相反，可以预测NMDA的激活将挽救暴露于同型半胱氨酸和相关化合物的胚胎。以下具体目标将检验这一假设。目的1，确定外源性NMDA拮抗剂如何与同型半胱氨酸相互作用，从而加剧对正常发育的破坏。目的2，测量NMDA的激活在多大程度上可以挽救用同型半胱氨酸和相关化合物处理过的胚胎。目的3：分析同型半胱氨酸和其他NMDA拮抗剂处理后胚胎基因表达的变化。的意义。这一建议提供了第一个关于异常发育的大量危险因素的机制的统一假设，这些因素的共同作用是抑制NMDA的功能。这些可能包括治疗药物、娱乐药物、环境污染物和营养不良的后遗症。一个共同的作用机制将允许这些因素以以前未曾预料到的方式相互作用，可能加剧它们各自的影响。通过了解这种相互作用机制，可以实现有效和全面的预防战略。