Interaction of teratogens in heart development

致畸剂在心脏发育中的相互作用

• 批准号: 7115376
• 负责人: THOMAS H. ROSENQUIST
• 金额: $ 24.55万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7115376
• 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.

现在通常假定在其原始细胞的共同起源中发现了共鸣和神经管缺陷之间众所周知的关系的生物学基础。但是，关于导致这些缺陷的机制尚无共识。通过补充叶酸，提供了高水平的保护，用于构成骨骼，其他神经rest和神经管缺陷，这意味着非同寻常的重要性过程敏感地取决于足够的叶酸供应。对于本提案，我们将检验以下假设：同型半胱氨酸是神经上皮层的综合子和其他衍生物的致畸。并且补充叶酸通过降低同型半胱氨酸的浓度可为胚胎提供保护，可通过充当NMDA受体（NMDA）拮抗剂来诱导孔子核和其他神经rest/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，以加剧致畸作用。相反，可以预测，NMDA的激活将营救暴露于同型半胱氨酸和相关化合物的胚胎。以下特定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破坏。 AIM 2，以测量NMDA激活的程度可以挽救用同型半胱氨酸和相关化合物处理的胚胎。目的3，分析用同型半胱氨酸和其他NMDA拮抗剂处理的胚胎中基因表达的变化。意义。该提案提供了第一个统一的假设，该假设是针对异常发育的大量风险因素的机制，其常见的效果是抑制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后遗症。一种共同的作用机制将使这些因素以先前未经使用的方式相互作用，从而加剧其各自的影响。通过了解这种互动机制可以实现有效而全面的预防策略。