HOMOCYSTEINE AND CONGENITAL HEART DEFECTS

补充叶酸可显著减少圆锥干、口面部和神经管畸形。氨基酸同型半胱氨酸随着叶酸缺乏而增加，而同型半胱氨酸本身的升高似乎是这些缺陷的一个危险因素。我们最近的研究提出了一个假设，即同型半胱氨酸可能通过作为N-甲基-D-天冬氨酸受体(NMDAR)的拮抗剂来扰乱神经脊和神经管的发育。事实上，一些最著名的神经脊和神经管畸形的危险因素也是NMDAR拮抗剂。目前的提议将检验同型半胱氨酸通过作为NMDAR拮抗剂诱导圆锥干和相关缺陷的假设。鸡和小鼠胚胎模型都将在这些实验中使用。这项提议有三个目的：目的1，验证NMDAR激动剂将挽救同型半胱氨酸处理的胚胎的假设，反之，外源性NMDAR拮抗剂将与同型半胱氨酸协同作用，加剧对正常发育的干扰。目的2，在同型半胱氨酸和外源性NMDAR拮抗剂干扰神经脊迁移和神经管关闭过程中关键基因表达的假说中，验证同型半胱氨酸和外源性NMDAR拮抗剂干扰关键基因表达的假设。目的：研究同型半胱氨酸和外源性NMDAR拮抗剂对神经脊细胞功能的影响。这项建议提供了第一个统一的假设，关于一系列重要的危险因素的异常发育的机制，包括治疗和娱乐药物，环境污染物和低叶酸。一种共同的行动机制将表明，这些因素可能以以前意想不到的方式相互作用。这项提议将开始探索基因/环境相互作用在这些异常诱导中的作用。尽管补充叶酸会导致较少的异常，但最有效和最全面的预防策略将来自于对异常发育基础机制的透彻了解。

Supplemental folic acid is associated with significant decreases in conotruncal, orofacial, and neural tube defects. The amino acid homocysteine increases with folate deficiency, and elevated homocysteine per se appears to be a risk factor for these defects. Our recent studies have led to the hypothesis that homocysteine may perturb neural crest and neural tube development by acting as an antagonist for the N-methyl-D-aspartate glutamate receptor (NMDAR). Indeed, some of the best known risk factors for neural crest and neural tube abnormalities also are NMDAR antagonist. The present proposal will test the hypothesis that homocysteine induces conotruncal and related defects by acting as an NMDAR antagonist. Both the chicken and the mouse embryo models will be employed in these experiments. There are three aims of this proposal: Aim 1, to test the hypotheses that NMDAR agonists will rescue homocysteine-treated embryos, and conversely, that exogenous NMDAR antagonists will interact synergistically with homocysteine to exacerbate the disruption of normal development. Aim 2, to test the hypothesis that homocysteine and exogenous NMDAR antagonists disrupt the expression of key genes during hypothesis that homocysteine and exogenous NMDAR antagonists disrupt the expression of key genes during neural crest migration and neural tube closure. Aim 2, to determine the effect of homocysteine and exogenous NMDAR antagonists on neural crest cell functions. This proposal offers the first unifying hypothesis regarding a mechanism for a set of important risk factors for abnormal development that includes therapeutic and recreational drugs, environmental contaminants, and low folate. A common mechanism of actions would show that these factors may interact in previous unsuspected ways. This proposal will begin to explore the role of gene/environment interactions in the induction of these abnormalities. Although folate supplements will result in fewer abnormalities, the most effective and comprehensive prevention strategies will come through a thorough understanding of the mechanisms that underlie abnormal development..