Interaction of teratogens in heart development

锥体和神经管缺陷之间众所周知的关系的生物学基础现在通常被认为是在它们的原始细胞的共同起源中找到的。然而，对于导致这些缺陷的机制还没有达成共识。补充叶酸可以为圆锥干、其他神经脊和神经管缺陷提供高水平的保护，这意味着一个未命名的特别重要的过程敏感地依赖于足够的叶酸供应。在目前的提案中，我们将检验如下假设，即同型半胱氨酸是圆锥干和其他神经上皮衍生物的致畸剂；补充叶酸通过降低同型半胱氨酸的浓度为胚胎提供保护，可以通过作为NMDA受体(NMDA)拮抗剂诱导圆锥干和其他神经脊/神经管衍生物的异常发育。通过这一机制，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；反过来，可以预测，NMDA的激活将挽救暴露在同型半胱氨酸及其相关化合物中的胚胎。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以加剧正常发育的中断。目的2，检测NMDA的激活在多大程度上可以挽救同型半胱氨酸及相关化合物处理的胚胎。目的分析同型半胱氨酸等NMDA拮抗剂对胚胎基因表达的影响。意义重大。这一建议提出了第一个统一的假设，即一系列异常发育的危险因素的机制，其共同作用是抑制NMDA的功能。这些药物可能包括治疗药物、娱乐药物、环境污染物和营养不良的后遗症。一种共同的行动机制将允许这些因素以以前未被怀疑的方式相互作用，潜在地加剧它们各自的影响。通过了解这种相互作用的机制，可以实现有效和全面的预防战略。

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.